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Prevalence and Characteristics of Pain in Patients Awaiting Lung Transplantation
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Journal of Pain and Symptom Management
Vol. 49 No. 3 March 2015
Original Article
Prevalence and Characteristics of Pain in Patients Awaiting Lung Transplantation Mireille Michel-Cherqui, MD, L ea Ley, MD, Barbara Szekely, MD, Jean-Franc¸ois Dreyfus, MD, PhD, and Marc Fischler, MD Department of Anesthesiology (M.M.-C., L.L., B.S., M.F.), Pain Management Unit (M.M.-C., B.S.) and Clinical Research Unit (J.-F.D.), H^o pital Foch, Suresnes; and University Versailles Saint-Quentin-en-Yvelines (M.M.-C., L.L., B.S., M.F.), Versailles, France
Abstract Context. Pain in patients awaiting lung transplantation is not well known. Objectives. This study prospectively investigated prevalence and characteristics of pain in these patients. Methods. Assessment, undertaken at the time of registration, comprised an interview, a physical examination by a painqualified anesthesiologist, and a questionnaire completed by the patient and investigator. This questionnaire included evaluation of pain (intensity, location, sensory and affective qualifications, and treatment), detection of neuropathic pain, and assessment of anxiety and depression. A patient was considered ‘‘with pain’’ when at least one of the following criteria was met: 1) positive answer to the question ‘‘Do you suffer regularly from pain?’’ and 2) score greater than 3 on at least one of three numeric pain scales (current, maximal, and average during the last eight days) ranging from 0 (no pain) to 10 (most severe pain imaginable). Results. One hundred forty-three patients were enrolled. Prevalence of pain was 59%. Three independent variables were correlated to the magnitude of the average pain score for the preceding eight days: female gender (P ¼ 0.003), cystic fibrosis (P ¼ 0.02), and depression score (P ¼ 0.02). Among the pain patients, 39% took analgesic drugs daily and 36% regularly but less than daily; 2% used opioids. Nineteen percent used nonpharmacological strategies (e.g., hypnosis, relaxation). Conclusion. This study highlights the prevalence of pain in this population and specific problems associated with pain such as anxiety and depression. Appropriate assessment and treatment of pain should be considered a component of pretransplantation management. J Pain Symptom Manage 2015;49:548e554. Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Pain, lung transplantation, cystic fibrosis
Introduction Lung transplantation is an accepted treatment for patients with end-stage lung disease, a clearly nonhomogeneous population of patients suffering mainly from cystic fibrosis (CF), emphysema, and lung fibrosis. Optimal preparation for transplantation is a goal for the multidisciplinary teams involved in their management. To date, few studies have assessed the prevalence of pain in this population of patients. Two studies focusing on pretransplant quality of life have shed
Address correspondence to: Marc Fischler, MD, Department of Anesthesiology, Foch Hospital, 40 rue Worth, 92151 Suresnes, France. E-mail: [email protected] Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
some light on the prevalence of pain in this population. Feltrim et al.1 assessed pain using the specific domain of the Short-Form 36 Health Survey and found that the limitations caused by pain significantly affected the bronchiectasis group and that the CF group was less affected. Dobbels et al.2 assessed the perceived health status among solid organ transplant candidates using the European Quality of Life (EuroQoL) scale; 67% of the lung transplant candidates reported moderate problems in the pain/discomfort dimension and 16% severe problems. No study has so far objectively
Accepted for publication: July 10, 2014.
0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2014.07.011
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Pain in Patients Before Lung Transplantation
assessed the features and management of pain in this population. We hypothesized that pain can be underdiagnosed and undertreated in these patients. Chronic pain is a common feature in Western populations.3 Its prevalence may be higher in patients on a lung transplant waiting list as a result of specific medications, physical limitations, and possible involvement of other organs.4e10 Moreover, many of them have had a chronic disease for their entire lives, and all of them have to cope with progressive deterioration in their quality of life while facing a fatal issue because of the uncertain availability of an organ. The risk of pulmonary exacerbation and death has been associated with higher levels of pain.11 Moreover, pain and decreased health-related quality of life have been shown to affect subsequent survival.12 The aims of this study were to determine the prevalence, management, and features of pain in a population of lung transplant candidates.
Methods Population This prospective study was approved by an Institutional Ethics Committee (Comit e Consultatif de Protection des Personnes dans la Recherche Biom edicale, H^ opital A. Par e, N SC 10 02 17, Boulogne Billancourt, France). From June 2008 to May 2011, consecutive patients who gave written informed consent were recruited for this study when registering on the waiting list for lung transplantation. Exclusion criteria were patients younger than 18 years and patients in unstable condition referred for emergency transplantation.
Questionnaires Pain assessment was undertaken during the two-day hospital stay required for registration. It comprised a 45-minute interview and physical examination by a pain-qualified anesthesiologist. Patients scored selfevaluation questionnaires; the investigator checked their answers and then asked additional questions to clarify location and management of pain. The paper questionnaire included three evaluations of pain (current pain, maximal pain in the last eight days, and average pain in the last eight days) on a numeric scale ranging from 0 (no pain) to 10 (most severe pain imaginable).13,14 A patient was considered ‘‘with pain’’ (as opposed to ‘‘pain free’’) when at least one of the following criteria was met: 1) positive answer to the question ‘‘Do you suffer regularly from pain ?’’ and 2) score greater than 3 on one or more of the three numeric pain scales. The description of location and nature of pain was assessed using diagrams of the body and answers to a questionnaire on pain location and circumstances. It
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allowed recognition of chest pain, back pain (lumbar and/or dorsal), headache or migraines, abdominal pain, limb pain, joint pain, pain related to scars and/or previous surgery, and procedure-related pain (mainly fiberoptic bronchoscopy). Sensory and affective qualifications of pain were assessed using the short-form ‘‘Questionnaire Douleur Saint-Antoine’’ (QDSA), a French adaptation15 of the short-form McGill Pain Questionnaire.16 Patients rate a list of 16 adjectives describing their pain for the presence and intensity; some of them are sensory (e.g., burning, throbbing) and others affective (e.g., depressing, exhausting). An answer of ‘‘moderate or severe’’ was considered a positive answer for each qualification.15,17 Neuropathic pain was ascertained using the DN4 questionnaire (Douleur Neuropathique en 4 questions), which is a 10-question screening tool. The first group of questions characterizes pain (burning, painful cold, electric shocks); the second group determines whether pain is associated with one or more of the following symptoms in the same area (tingling, pins and needles, numbness, itching, and if it is increased by rubbing skin in the painful area). In addition, two items require a physical examination to reveal if there is hypesthesia to touch and pinprick in the painful area. Each item scores 1, and if the total score is 4 or higher, the pain is likely to be neuropathic.18 Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS).19 The HADS is a 14-item scale; seven of the items relate to anxiety and seven to depression. Each item on the questionnaire is scored from 0 to 3; consequently, a patient can score from 0 to 21 for depression and/ or for anxiety. The cutoff value for each subscale is still under discussion but, in accordance with frequent recommendations, we considered that a total score of above 10 was indicative of a clinical diagnosis of moderate-to-severe anxiety or depression.20 Regarding pharmacological pain management, analgesic medications taken by the patients were assigned to one of the three steps of the World Health Organization’s (WHO) analgesic ladder.21 Only medications taken daily or regularly but less frequently than daily were recorded. Nonpharmacological treatments were ascertained by an open-ended question. Relaxation, hypnosis, mindfulness-based therapy, transcutaneous electrical nerve stimulation, and ‘‘other’’ were listed as possible answers. Active physical therapy and reconditioning were recorded as absent or present.
Statistical Analysis
Descriptive statistics provide mean SD (range) for normally distributed continuous variables and median (first third quartiles) for ordinal variables. Counts
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Table 1 Principal Characteristics of All Patients (n ¼ 143) Characteristic Age (yrs) Gender (female/male) Type of pathology Cystic fibrosis Emphysema Fibrosis Other Patients with paina Significant anxiety scoreb Significant depression scoreb
Mean SD (Range) or n (%) 39.2 13.6 (19e65) 69 (48)/74 (52) 73 38 19 13 84 51 14
(51) (27) (13) (9) (59) (36) (10)
a A patient was considered ‘‘with pain’’ when at least one of the following criteria was met: 1) positive answer to the question ‘‘Do you suffer regularly from pain?’’ and 2) score >3 on one or more of the three numeric pain scales. b A total score greater than 10 signals a clinical diagnosis of moderate-to-severe anxiety or depression.
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the transplantation list. None had a noninclusion criterion, and none refused to be enrolled.
Patient Characteristics The main characteristics of all patients are summarized in Table 1. Among the 143 patients who were included in this prospective study, 69 were women (48%) and 74 men (52%); 84 (59%) were considered with pain, 51 (36%) presented a significant anxiety score, and 14 (10%) a significant depression score. Seventy-three (51%) presented with CF, 38 (27%) emphysema, 19 (13%) fibrosis, and 13 (9%) other pathologies. The mean age was 39.2 13.6 years (range 19e65).
Prevalence of Pain and percentages are given for discrete variables. Probabilities were obtained by randomization t-test with 10,000 permutations for continuous variables and Fisher’s exact test for categorical variables, with Bonferroni-Simes correction if relevant. Spearman’s correlation coefficient was used to assess the relationship between pain scores. Backward multiple regression was used to relate the average pain score to six explanatory variables: age, gender, anxiety score, depression score, diabetes, and pathology leading to transplantation. The latter two were retrieved from hospital medical charts completed by the transplantation team. Number Crunching Statistical Software 9 (NCSS LLC, Kaysville, UT) and R 2.14.2 software (Vienna, Austria) were used for the analyses.
Results During the study period, 143 adult patients underwent evaluation at the time of their registration on
Eighty-two patients (57%) replied positively to the question: ‘‘Do you suffer regularly from pain?’’ Moreover, two patients who answered ‘‘no’’ to this question reported a pain score greater than 3 on one of the three numeric pain scales. Consequently, 84 patients (59%) were considered with pain. The main characteristics of patients with pain (Painþ) and pain-free patients (Pain) are summarized in Table 2. Median (first third quartiles) values for current, average, and maximal pain scale scores were 1 (0e3), 3 (1e5), and 5 (3e7), respectively, among patients with pain. There is a strong correlation between current and maximal pain (Spearman r ¼ 0.72, P < 0.0001), current and average pain (Spearman r ¼ 0.76, P < 0.0001), and maximal and average pain (Spearman r ¼ 0.90, P < 0.0001). Statistically significant differences (P < 0.0001) were found for all pain scores between Painþ and Pain patients (Table 2). Based on a cutoff value of >3, and taking into account that patients could score a significant pain score
Table 2 Characteristics of Pain Patients and Pain-Free Patients Characteristic Age (yrs) Gender (female/male) Type of pathology Cystic fibrosis Emphysema Fibrosis Other Diabetes Anxiety score Significant anxiety scorea Depression score Significant depression scorea Current pain Average pain Maximal pain
Painþ, n ¼ 84
Pain, n ¼ 59
36.7 13.6 (19e61) 52 (62)/32 (38)
41.6 13.8 (20e65) 17 (29)/42 (71)
52 (62) 17 (20) 8 (9) 7 (8) 28 (33) 9.9 4.2 (2e20) 40 (48) 6.7 3.6 (0e21) 12 (14) 1 (0e3) 3 (1e5) 5 (3e7)
21 (36) 21 (36) 11 (19) 6 (10) 7 (12) 7.4 4.7 (0e21) 11 (19) 5.2 3.9 (0e21) 2 (3) 0 (0e0) 0 (0e0) 0 (0e0)
P-value 0.03 0.0002 0.003 0.05 0.14 0.78 0.004 0.002 <0.001 0.03 0.05 <0.0001 <0.0001 <0.0001
Results are presented as mean SD (range), count (percentage), and median (first third quartiles). P-values obtained by randomization t-test with 10,000 permutations for continuous variables and by Fisher’s exact test for categorical variables, with Bonferroni-Simes correction if relevant. Painþ ¼ patients suffering from pain; Pain ¼ patients not suffering from pain. a A total score greater than 10 signals a clinical diagnosis of moderate-to-severe anxiety or depression.
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Table 3 Risk Factors for Pain (Multiple Regression Analysis) Regression Coefficient Variable
Regression Coefficient
SD
Lower 95% CI
Upper 95% CI
P-value
0.74 0.11 0.96
0.317 0.042 0.318
0.12 0.02 0.34
1.37 0.19 1.59
0.02 0.02 0.003
Cystic fibrosis present Depression score Female gender
SD ¼ standard deviation; CI ¼ confidence interval.
in one, two, or all three scales, 20 patients (14%) were currently in pain, 54 (38%) had maximal pain over 3 during the past eight days, and 31 (22%) had been, on average, in pain during the last eight days. Age, gender, type of pathology (CF), diabetes, and anxiety and depression scores differed significantly between Painþ and Painpatients (Table 2).
Multiple Regression Analysis A multiple regression analysis was conducted to relate the magnitude of the average pain score for the preceding eight days to demographic and clinical parameters. Three independent variables were correlated to pain: female gender (P ¼ 0.003), CF (P ¼ 0.02), and depression score (P ¼ 0.02). A model retaining only these variables explains 12% of the pain scores (Table 3). CF increased the score by about 0.74 points, female gender increased the score by about 0.96 points, and an increase of one unit of depression score increased the pain score by about 0.11 points.
Management of Pain Among pain patients, 25% took no drugs, 39% took analgesic drugs daily, and 36% took analgesic drugs regularly but less frequently than daily. Among the 33 patients taking analgesics, 24 (73%) took WHO Level 1 analgesics, such as paracetamol (acetaminophen), 10 (30%) took WHO Level 2 analgesics, such as paracetamol-codeine or tramadol, and two (6%) used opioids (WHO Level 3). One patient was taking gabapentin and another a low dose of amitriptyline for neuropathic pain, and five took triptans for migraine. Sixteen patients with pain (19%) used nondrug pain treatment, 11 of them on a regular basis. Four of them used transcutaneous electrical nerve stimulation on a daily basis for back pain, and seven had attended relaxation or mindfulness-based therapy or hypnosis training during the past six months. Finally, among pain patients, 14 patients (17%) underwent physical therapy and reconditioning at least once a week.
Discussion Pain Description On QDSA, the most common sensory qualifiers for pain were ‘‘throbbing’’ and ‘‘heavy‘‘ (both at 23%), and the most common affective qualifiers were ‘‘exhausting’’ (33%) then ‘‘irritating’’ and ‘‘unbearable’’ (both at 16%). Locations and type of pain were reported and are summarized in Table 4.
This study provides a comprehensive picture of pain and its characteristics in a population of patients enlisted for lung transplantation. Prevalence of pain was 59%, which makes it a major health concern. Although the underlying respiratory disease was variable, our study group was homogeneous as all patients presented with end-stage respiratory disease.
Table 4 Location and Type of Pain for All Patients Suffering Pain and Those With CF Painþ
Painþ CF
Painþ CFþ
Location and Type of Pain
n ¼ 84
n ¼ 32
n ¼ 52
Back Head Joint Chest Abdomen Limb Scar Procedural pain Neuropathic pain
38 31 30 28 18 17 2 8 6
11 11 10 9 6 6 0 3 3
27 20 20 19 12 11 2 5 3
(45) (37) (36) (33) (21) (20) (2) (9) (7)
(34) (34) (34) (28) (19) (19) (0) (9) (9)
(52) (38) (38) (37) (23) (21) (4) (10) (6)
P-value for Painþ CFþ vs. Painþ CF 0.18 0.82 0.64 0.48 0.79 >0.9 0.52 >0.9 0.67
CF ¼ cystic fibrosis. Results are presented as count (percentage); P-values from Fisher’s exact test (comparison between painþ CFþ patients and painþ CF patients). Painþ ¼ all patients with pain; Painþ CFþ ¼ cystic fibrosis patients suffering from pain; Painþ CF ¼ patients suffering from pain, other diagnoses.
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Prevalence of pain among female patients was 75% (52/69) and 43% (32/74) among male patients. Gender is one of the three pain correlates found in the multiple regression analysis. In the general population, the difference in pain prevalence according to gender has been extensively discussed, and a metaanalysis studying the sensitivity to a noxious stimulus found women to be slightly more pain sensitive than men.22 Women generally report more chronic pain, such as fibromyalgia or arthritis, than men, the difference remaining difficult to explain. Cultural differences, gender-related expectations for pain, difference in concentration of sex hormones but also different neuronal organizations, and opioid-receptor density may account for differences in pain sensitivity.23,24 However, no difference between genders in the prevalence of pain in patients with end-stage pulmonary failure has been mentioned previously, and we have no explanation for the major difference we found. We tried to assess which demographic and/or clinical parameters were related to the magnitude of pain in pretransplant patients. Only female gender, CF, and depression appear to be pain correlates according to the multiple regression analysis. Two statistically significant variables, anxiety and depression, are more intricate (triggered by pain and/or leading to a higher pain score). Moreover, only 12% of the total variability of the average pain scores can be explained by female gender, pathology, and depression. Pain was more prevalent in CF patients, which is consistent with previous studies that report a high prevalence of pain in this population at various stages of the disease. Prevalence of pain was much higher among diabetic patients (80%) compared with nondiabetic patients (52%), but this was not found to be a pain correlate in the multivariate analysis. Although painful diabetic peripheral neuropathy has been described in about 20% of patients with Type 2 diabetes, a higher prevalence of other types of pain had not been reported in these patients.25 Similar to the study by Sermet-Gaudelus et al.,10 we found that patients with pain were significantly younger, but age did not appear to be independently correlated to pain severity in the multivariate analysis of our patients. High anxiety scores were recorded in our population as 36% of all our patients presented moderateto-severe anxiety. Lung function and anxiety symptoms are related, and a recent study suggested that, in addition to its relation to reduced lung function, the subjective experience of breathing discomfort also may influence, or be influenced by, anxiety.26 Anxiety scores were much higher among our patients with pain as 48% had scores that are commonly considered as evidencing clinical anxiety
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vs. 19% in pain-free patients. It is difficult to establish if pain per se generates anxiety or if anxious patients are more sensitive to pain, or prone to report it, or to allow installation of chronic pain. Common factors such as inability to cope, lack of internal resources or biological changes may play a role, but anxiety is frequently increased in patients with chronic pain and is usually reported in 20% to 40% of them.27 Some facts may explain this high level of anxiety in our population. First, we studied a population with end-stage pulmonary disease registered on the waiting list for transplantation. Second, our consultation took place at the time patients registered on this list, which could have led to major emotional distress. Last, anxiety seems to increase with age, which should be taken into account as our population was older than that of other studies. Nevertheless, as pretransplantation anxiety has been shown to predict post-transplantation psychological status and quality of life,28 we contend that these results should be taken into account in our routine practice. The WHO estimates that 5% to 10% of the population at any given time is suffering from identifiable depression needing psychiatric or psychosocial intervention.29 This rate is close to the 10% incidence of depression found among our patients, and similar rates have been reported by others.30 Pain severity has been considered to be a predictor of depressive symptoms in a chronic obstructive or interstitial pulmonary disease population.31,32 It has recently been shown that a high depression score before transplantation (using the Beck Depression Inventory) was correlated to poor outcome.33 In our study, there was a significant relationship between pain and depression (P ¼ 0.01), and according to the multiple regression study, an increase of 10 points in the depression score leads to an average of 1.1 point increase in pain scores. This result also should be taken into account in our practice: depression should be systematically evaluated, treated by pharmacological or nonpharmacological therapies, and improvement must be followed up. Back pain was the pain most frequently experienced by our patients. Back pain is mostly of musculoskeletal origin and related to thoracic kyphosis in CF patients and postural abnormalities and osteoporosis in all the patients.34,35 Osteoporosis, which is mainly related to loss of body mass, inability to exercise, and frequent use of corticoids, may lead to compression fractures of thoracic and lumbar vertebrae.36 Fifty-eight percent of our patients with pain, or 44% of all our patients, reported difficulties in walking that impacted on their autonomy. However, only 19% of all patients underwent regular physical therapy and reconditioning. This rate is consistent with the poor participation of this population in daily physical activity.37
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Classically, headache is linked to sinusitis, nasal polyps in CF patients, or hypercapnia in end-stage lung disease. Chest pain could be muscular or related to pleural lesions, a broken rib, or pneumothorax and was frequently reported. Abdominal pain is related to distal intestinal obstruction syndrome, nonobservance of pancreatic extract treatment, or gastroesophageal reflux; it is known to occur more frequently in young CF patients. Our patients presented a low prevalence of abdominal pain compared with other CF studies with a high proportion of young people. Procedural pain was reported by only 7% of all patients. This prevalence is much lower than that in some other studies where it can be as high as 78%.10 Although we can stress the good quality of care for all the potentially painful procedures in our institution, some cases may have been missed as some procedures are performed at long intervals and patients were asked to report procedural pain for the last week. However, although pain mechanisms could be different in our groups of patients, we did not find any difference in pain location when we compared pain patients with CF with pain patients without CF. Only 39% of the patients reporting pain took analgesics. This is lower than the proportion found in other studies, where 50% to 68% of patients took analgesic drugs.9,10 Many patients, when asked why they did not take analgesic agents, answered that they did not find them efficient while having side effects; others did not want to add these drugs to an already long list of medications. Interestingly, Festini et al.9 had previously reported that among 225 CF patients who reported pain symptoms, 26% did nothing to fight the pain. Nonpharmacological approaches are difficult to analyze as techniques as different as homeopathy, transcutaneous electrical nerve stimulation, relaxation, or hypnosis could be reported by patients. Nevertheless, only 19% of our pain patients had at least one or more attempt at these approaches. Although this percentage is close to that reported by others,9,10 it is much lower than those of centers where pain patients are systematically referred to a pain treatment department and where noninvasive forms of pain control are more widely used and considered as first-line therapies.5 Alternative therapies also could be used for anxiety and depressive conditions, but only one of our patients reported relaxation therapy for relief of anxiety. Only two patients in our population reported use of opioids. Opioid use in this kind of population varies widely depending on country and hospital. In France, Sermet-Gaudelus et al.10 noted that of 89 adults with pain, only one patient took opioids, whereas a North American study reported that 53% of 78 patients with severe CF were taking opioids for pain.5 This difference could be the
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result of different risk appraisals for tolerance manifestations, postoperative hyperalgesia, or side effects such as constipation or respiratory impairment.38 This study has several limitations that must be considered. Patients were considered ‘‘with pain’’ if they answered ‘‘yes’’ to the question ‘‘Do you suffer regularly from pain?’’ Patients were also considered ‘‘with pain’’ if they answered ‘‘no’’ to the question but had a score greater than 3 on one or more of the three scales. The cutoff of >3 is usually considered to separate mild pain not requiring any systematic treatment from more severe pain requiring a systematic treatment. Although a physical examination was conducted by a pain-qualified anesthesiologist, it was most of the time difficult to identify the cause of pain. For example, dorsal pain, which is very frequent, could be the result of the association of kyphotic posture, vertebral wedging secondary to osteoporosis, and pleurisy, and also could be worsened by physiotherapy. Another limit of our study is that we did not ask the patient to indicate the percentage of relief provided by pain treatments or medications. Consequently, this could explain that some patients took analgesics less frequently than other patients because they were not satisfied.
Conclusion This study highlights the prevalence of pain in our patients and specific problems associated with pain such as anxiety and depression. Appropriate assessment and treatment of pain using pharmacological, psychological support, and/or complementary therapies must be considered a significant component of the management of these patients.
Disclosures and Acknowledgments This research was supported by a grant (TP0904) from the ‘‘Vaincre la Mucoviscidose’’ association. The funding source was not involved in the conduct of the study or development of the submission. The authors declare no conflicts of interest.
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Original Article
Prevalence and Characteristics of Pain in Patients Awaiting Lung Transplantation Mireille Michel-Cherqui, MD, L ea Ley, MD, Barbara Szekely, MD, Jean-Franc¸ois Dreyfus, MD, PhD, and Marc Fischler, MD Department of Anesthesiology (M.M.-C., L.L., B.S., M.F.), Pain Management Unit (M.M.-C., B.S.) and Clinical Research Unit (J.-F.D.), H^o pital Foch, Suresnes; and University Versailles Saint-Quentin-en-Yvelines (M.M.-C., L.L., B.S., M.F.), Versailles, France
Abstract Context. Pain in patients awaiting lung transplantation is not well known. Objectives. This study prospectively investigated prevalence and characteristics of pain in these patients. Methods. Assessment, undertaken at the time of registration, comprised an interview, a physical examination by a painqualified anesthesiologist, and a questionnaire completed by the patient and investigator. This questionnaire included evaluation of pain (intensity, location, sensory and affective qualifications, and treatment), detection of neuropathic pain, and assessment of anxiety and depression. A patient was considered ‘‘with pain’’ when at least one of the following criteria was met: 1) positive answer to the question ‘‘Do you suffer regularly from pain?’’ and 2) score greater than 3 on at least one of three numeric pain scales (current, maximal, and average during the last eight days) ranging from 0 (no pain) to 10 (most severe pain imaginable). Results. One hundred forty-three patients were enrolled. Prevalence of pain was 59%. Three independent variables were correlated to the magnitude of the average pain score for the preceding eight days: female gender (P ¼ 0.003), cystic fibrosis (P ¼ 0.02), and depression score (P ¼ 0.02). Among the pain patients, 39% took analgesic drugs daily and 36% regularly but less than daily; 2% used opioids. Nineteen percent used nonpharmacological strategies (e.g., hypnosis, relaxation). Conclusion. This study highlights the prevalence of pain in this population and specific problems associated with pain such as anxiety and depression. Appropriate assessment and treatment of pain should be considered a component of pretransplantation management. J Pain Symptom Manage 2015;49:548e554. Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved. Key Words Pain, lung transplantation, cystic fibrosis
Introduction Lung transplantation is an accepted treatment for patients with end-stage lung disease, a clearly nonhomogeneous population of patients suffering mainly from cystic fibrosis (CF), emphysema, and lung fibrosis. Optimal preparation for transplantation is a goal for the multidisciplinary teams involved in their management. To date, few studies have assessed the prevalence of pain in this population of patients. Two studies focusing on pretransplant quality of life have shed
Address correspondence to: Marc Fischler, MD, Department of Anesthesiology, Foch Hospital, 40 rue Worth, 92151 Suresnes, France. E-mail: [email protected] Ó 2015 American Academy of Hospice and Palliative Medicine. Published by Elsevier Inc. All rights reserved.
some light on the prevalence of pain in this population. Feltrim et al.1 assessed pain using the specific domain of the Short-Form 36 Health Survey and found that the limitations caused by pain significantly affected the bronchiectasis group and that the CF group was less affected. Dobbels et al.2 assessed the perceived health status among solid organ transplant candidates using the European Quality of Life (EuroQoL) scale; 67% of the lung transplant candidates reported moderate problems in the pain/discomfort dimension and 16% severe problems. No study has so far objectively
Accepted for publication: July 10, 2014.
0885-3924/$ - see front matter http://dx.doi.org/10.1016/j.jpainsymman.2014.07.011
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Pain in Patients Before Lung Transplantation
assessed the features and management of pain in this population. We hypothesized that pain can be underdiagnosed and undertreated in these patients. Chronic pain is a common feature in Western populations.3 Its prevalence may be higher in patients on a lung transplant waiting list as a result of specific medications, physical limitations, and possible involvement of other organs.4e10 Moreover, many of them have had a chronic disease for their entire lives, and all of them have to cope with progressive deterioration in their quality of life while facing a fatal issue because of the uncertain availability of an organ. The risk of pulmonary exacerbation and death has been associated with higher levels of pain.11 Moreover, pain and decreased health-related quality of life have been shown to affect subsequent survival.12 The aims of this study were to determine the prevalence, management, and features of pain in a population of lung transplant candidates.
Methods Population This prospective study was approved by an Institutional Ethics Committee (Comit e Consultatif de Protection des Personnes dans la Recherche Biom edicale, H^ opital A. Par e, N SC 10 02 17, Boulogne Billancourt, France). From June 2008 to May 2011, consecutive patients who gave written informed consent were recruited for this study when registering on the waiting list for lung transplantation. Exclusion criteria were patients younger than 18 years and patients in unstable condition referred for emergency transplantation.
Questionnaires Pain assessment was undertaken during the two-day hospital stay required for registration. It comprised a 45-minute interview and physical examination by a pain-qualified anesthesiologist. Patients scored selfevaluation questionnaires; the investigator checked their answers and then asked additional questions to clarify location and management of pain. The paper questionnaire included three evaluations of pain (current pain, maximal pain in the last eight days, and average pain in the last eight days) on a numeric scale ranging from 0 (no pain) to 10 (most severe pain imaginable).13,14 A patient was considered ‘‘with pain’’ (as opposed to ‘‘pain free’’) when at least one of the following criteria was met: 1) positive answer to the question ‘‘Do you suffer regularly from pain ?’’ and 2) score greater than 3 on one or more of the three numeric pain scales. The description of location and nature of pain was assessed using diagrams of the body and answers to a questionnaire on pain location and circumstances. It
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allowed recognition of chest pain, back pain (lumbar and/or dorsal), headache or migraines, abdominal pain, limb pain, joint pain, pain related to scars and/or previous surgery, and procedure-related pain (mainly fiberoptic bronchoscopy). Sensory and affective qualifications of pain were assessed using the short-form ‘‘Questionnaire Douleur Saint-Antoine’’ (QDSA), a French adaptation15 of the short-form McGill Pain Questionnaire.16 Patients rate a list of 16 adjectives describing their pain for the presence and intensity; some of them are sensory (e.g., burning, throbbing) and others affective (e.g., depressing, exhausting). An answer of ‘‘moderate or severe’’ was considered a positive answer for each qualification.15,17 Neuropathic pain was ascertained using the DN4 questionnaire (Douleur Neuropathique en 4 questions), which is a 10-question screening tool. The first group of questions characterizes pain (burning, painful cold, electric shocks); the second group determines whether pain is associated with one or more of the following symptoms in the same area (tingling, pins and needles, numbness, itching, and if it is increased by rubbing skin in the painful area). In addition, two items require a physical examination to reveal if there is hypesthesia to touch and pinprick in the painful area. Each item scores 1, and if the total score is 4 or higher, the pain is likely to be neuropathic.18 Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS).19 The HADS is a 14-item scale; seven of the items relate to anxiety and seven to depression. Each item on the questionnaire is scored from 0 to 3; consequently, a patient can score from 0 to 21 for depression and/ or for anxiety. The cutoff value for each subscale is still under discussion but, in accordance with frequent recommendations, we considered that a total score of above 10 was indicative of a clinical diagnosis of moderate-to-severe anxiety or depression.20 Regarding pharmacological pain management, analgesic medications taken by the patients were assigned to one of the three steps of the World Health Organization’s (WHO) analgesic ladder.21 Only medications taken daily or regularly but less frequently than daily were recorded. Nonpharmacological treatments were ascertained by an open-ended question. Relaxation, hypnosis, mindfulness-based therapy, transcutaneous electrical nerve stimulation, and ‘‘other’’ were listed as possible answers. Active physical therapy and reconditioning were recorded as absent or present.
Statistical Analysis
Descriptive statistics provide mean SD (range) for normally distributed continuous variables and median (first third quartiles) for ordinal variables. Counts
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Table 1 Principal Characteristics of All Patients (n ¼ 143) Characteristic Age (yrs) Gender (female/male) Type of pathology Cystic fibrosis Emphysema Fibrosis Other Patients with paina Significant anxiety scoreb Significant depression scoreb
Mean SD (Range) or n (%) 39.2 13.6 (19e65) 69 (48)/74 (52) 73 38 19 13 84 51 14
(51) (27) (13) (9) (59) (36) (10)
a A patient was considered ‘‘with pain’’ when at least one of the following criteria was met: 1) positive answer to the question ‘‘Do you suffer regularly from pain?’’ and 2) score >3 on one or more of the three numeric pain scales. b A total score greater than 10 signals a clinical diagnosis of moderate-to-severe anxiety or depression.
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the transplantation list. None had a noninclusion criterion, and none refused to be enrolled.
Patient Characteristics The main characteristics of all patients are summarized in Table 1. Among the 143 patients who were included in this prospective study, 69 were women (48%) and 74 men (52%); 84 (59%) were considered with pain, 51 (36%) presented a significant anxiety score, and 14 (10%) a significant depression score. Seventy-three (51%) presented with CF, 38 (27%) emphysema, 19 (13%) fibrosis, and 13 (9%) other pathologies. The mean age was 39.2 13.6 years (range 19e65).
Prevalence of Pain and percentages are given for discrete variables. Probabilities were obtained by randomization t-test with 10,000 permutations for continuous variables and Fisher’s exact test for categorical variables, with Bonferroni-Simes correction if relevant. Spearman’s correlation coefficient was used to assess the relationship between pain scores. Backward multiple regression was used to relate the average pain score to six explanatory variables: age, gender, anxiety score, depression score, diabetes, and pathology leading to transplantation. The latter two were retrieved from hospital medical charts completed by the transplantation team. Number Crunching Statistical Software 9 (NCSS LLC, Kaysville, UT) and R 2.14.2 software (Vienna, Austria) were used for the analyses.
Results During the study period, 143 adult patients underwent evaluation at the time of their registration on
Eighty-two patients (57%) replied positively to the question: ‘‘Do you suffer regularly from pain?’’ Moreover, two patients who answered ‘‘no’’ to this question reported a pain score greater than 3 on one of the three numeric pain scales. Consequently, 84 patients (59%) were considered with pain. The main characteristics of patients with pain (Painþ) and pain-free patients (Pain) are summarized in Table 2. Median (first third quartiles) values for current, average, and maximal pain scale scores were 1 (0e3), 3 (1e5), and 5 (3e7), respectively, among patients with pain. There is a strong correlation between current and maximal pain (Spearman r ¼ 0.72, P < 0.0001), current and average pain (Spearman r ¼ 0.76, P < 0.0001), and maximal and average pain (Spearman r ¼ 0.90, P < 0.0001). Statistically significant differences (P < 0.0001) were found for all pain scores between Painþ and Pain patients (Table 2). Based on a cutoff value of >3, and taking into account that patients could score a significant pain score
Table 2 Characteristics of Pain Patients and Pain-Free Patients Characteristic Age (yrs) Gender (female/male) Type of pathology Cystic fibrosis Emphysema Fibrosis Other Diabetes Anxiety score Significant anxiety scorea Depression score Significant depression scorea Current pain Average pain Maximal pain
Painþ, n ¼ 84
Pain, n ¼ 59
36.7 13.6 (19e61) 52 (62)/32 (38)
41.6 13.8 (20e65) 17 (29)/42 (71)
52 (62) 17 (20) 8 (9) 7 (8) 28 (33) 9.9 4.2 (2e20) 40 (48) 6.7 3.6 (0e21) 12 (14) 1 (0e3) 3 (1e5) 5 (3e7)
21 (36) 21 (36) 11 (19) 6 (10) 7 (12) 7.4 4.7 (0e21) 11 (19) 5.2 3.9 (0e21) 2 (3) 0 (0e0) 0 (0e0) 0 (0e0)
P-value 0.03 0.0002 0.003 0.05 0.14 0.78 0.004 0.002 <0.001 0.03 0.05 <0.0001 <0.0001 <0.0001
Results are presented as mean SD (range), count (percentage), and median (first third quartiles). P-values obtained by randomization t-test with 10,000 permutations for continuous variables and by Fisher’s exact test for categorical variables, with Bonferroni-Simes correction if relevant. Painþ ¼ patients suffering from pain; Pain ¼ patients not suffering from pain. a A total score greater than 10 signals a clinical diagnosis of moderate-to-severe anxiety or depression.
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Table 3 Risk Factors for Pain (Multiple Regression Analysis) Regression Coefficient Variable
Regression Coefficient
SD
Lower 95% CI
Upper 95% CI
P-value
0.74 0.11 0.96
0.317 0.042 0.318
0.12 0.02 0.34
1.37 0.19 1.59
0.02 0.02 0.003
Cystic fibrosis present Depression score Female gender
SD ¼ standard deviation; CI ¼ confidence interval.
in one, two, or all three scales, 20 patients (14%) were currently in pain, 54 (38%) had maximal pain over 3 during the past eight days, and 31 (22%) had been, on average, in pain during the last eight days. Age, gender, type of pathology (CF), diabetes, and anxiety and depression scores differed significantly between Painþ and Painpatients (Table 2).
Multiple Regression Analysis A multiple regression analysis was conducted to relate the magnitude of the average pain score for the preceding eight days to demographic and clinical parameters. Three independent variables were correlated to pain: female gender (P ¼ 0.003), CF (P ¼ 0.02), and depression score (P ¼ 0.02). A model retaining only these variables explains 12% of the pain scores (Table 3). CF increased the score by about 0.74 points, female gender increased the score by about 0.96 points, and an increase of one unit of depression score increased the pain score by about 0.11 points.
Management of Pain Among pain patients, 25% took no drugs, 39% took analgesic drugs daily, and 36% took analgesic drugs regularly but less frequently than daily. Among the 33 patients taking analgesics, 24 (73%) took WHO Level 1 analgesics, such as paracetamol (acetaminophen), 10 (30%) took WHO Level 2 analgesics, such as paracetamol-codeine or tramadol, and two (6%) used opioids (WHO Level 3). One patient was taking gabapentin and another a low dose of amitriptyline for neuropathic pain, and five took triptans for migraine. Sixteen patients with pain (19%) used nondrug pain treatment, 11 of them on a regular basis. Four of them used transcutaneous electrical nerve stimulation on a daily basis for back pain, and seven had attended relaxation or mindfulness-based therapy or hypnosis training during the past six months. Finally, among pain patients, 14 patients (17%) underwent physical therapy and reconditioning at least once a week.
Discussion Pain Description On QDSA, the most common sensory qualifiers for pain were ‘‘throbbing’’ and ‘‘heavy‘‘ (both at 23%), and the most common affective qualifiers were ‘‘exhausting’’ (33%) then ‘‘irritating’’ and ‘‘unbearable’’ (both at 16%). Locations and type of pain were reported and are summarized in Table 4.
This study provides a comprehensive picture of pain and its characteristics in a population of patients enlisted for lung transplantation. Prevalence of pain was 59%, which makes it a major health concern. Although the underlying respiratory disease was variable, our study group was homogeneous as all patients presented with end-stage respiratory disease.
Table 4 Location and Type of Pain for All Patients Suffering Pain and Those With CF Painþ
Painþ CF
Painþ CFþ
Location and Type of Pain
n ¼ 84
n ¼ 32
n ¼ 52
Back Head Joint Chest Abdomen Limb Scar Procedural pain Neuropathic pain
38 31 30 28 18 17 2 8 6
11 11 10 9 6 6 0 3 3
27 20 20 19 12 11 2 5 3
(45) (37) (36) (33) (21) (20) (2) (9) (7)
(34) (34) (34) (28) (19) (19) (0) (9) (9)
(52) (38) (38) (37) (23) (21) (4) (10) (6)
P-value for Painþ CFþ vs. Painþ CF 0.18 0.82 0.64 0.48 0.79 >0.9 0.52 >0.9 0.67
CF ¼ cystic fibrosis. Results are presented as count (percentage); P-values from Fisher’s exact test (comparison between painþ CFþ patients and painþ CF patients). Painþ ¼ all patients with pain; Painþ CFþ ¼ cystic fibrosis patients suffering from pain; Painþ CF ¼ patients suffering from pain, other diagnoses.
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Prevalence of pain among female patients was 75% (52/69) and 43% (32/74) among male patients. Gender is one of the three pain correlates found in the multiple regression analysis. In the general population, the difference in pain prevalence according to gender has been extensively discussed, and a metaanalysis studying the sensitivity to a noxious stimulus found women to be slightly more pain sensitive than men.22 Women generally report more chronic pain, such as fibromyalgia or arthritis, than men, the difference remaining difficult to explain. Cultural differences, gender-related expectations for pain, difference in concentration of sex hormones but also different neuronal organizations, and opioid-receptor density may account for differences in pain sensitivity.23,24 However, no difference between genders in the prevalence of pain in patients with end-stage pulmonary failure has been mentioned previously, and we have no explanation for the major difference we found. We tried to assess which demographic and/or clinical parameters were related to the magnitude of pain in pretransplant patients. Only female gender, CF, and depression appear to be pain correlates according to the multiple regression analysis. Two statistically significant variables, anxiety and depression, are more intricate (triggered by pain and/or leading to a higher pain score). Moreover, only 12% of the total variability of the average pain scores can be explained by female gender, pathology, and depression. Pain was more prevalent in CF patients, which is consistent with previous studies that report a high prevalence of pain in this population at various stages of the disease. Prevalence of pain was much higher among diabetic patients (80%) compared with nondiabetic patients (52%), but this was not found to be a pain correlate in the multivariate analysis. Although painful diabetic peripheral neuropathy has been described in about 20% of patients with Type 2 diabetes, a higher prevalence of other types of pain had not been reported in these patients.25 Similar to the study by Sermet-Gaudelus et al.,10 we found that patients with pain were significantly younger, but age did not appear to be independently correlated to pain severity in the multivariate analysis of our patients. High anxiety scores were recorded in our population as 36% of all our patients presented moderateto-severe anxiety. Lung function and anxiety symptoms are related, and a recent study suggested that, in addition to its relation to reduced lung function, the subjective experience of breathing discomfort also may influence, or be influenced by, anxiety.26 Anxiety scores were much higher among our patients with pain as 48% had scores that are commonly considered as evidencing clinical anxiety
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vs. 19% in pain-free patients. It is difficult to establish if pain per se generates anxiety or if anxious patients are more sensitive to pain, or prone to report it, or to allow installation of chronic pain. Common factors such as inability to cope, lack of internal resources or biological changes may play a role, but anxiety is frequently increased in patients with chronic pain and is usually reported in 20% to 40% of them.27 Some facts may explain this high level of anxiety in our population. First, we studied a population with end-stage pulmonary disease registered on the waiting list for transplantation. Second, our consultation took place at the time patients registered on this list, which could have led to major emotional distress. Last, anxiety seems to increase with age, which should be taken into account as our population was older than that of other studies. Nevertheless, as pretransplantation anxiety has been shown to predict post-transplantation psychological status and quality of life,28 we contend that these results should be taken into account in our routine practice. The WHO estimates that 5% to 10% of the population at any given time is suffering from identifiable depression needing psychiatric or psychosocial intervention.29 This rate is close to the 10% incidence of depression found among our patients, and similar rates have been reported by others.30 Pain severity has been considered to be a predictor of depressive symptoms in a chronic obstructive or interstitial pulmonary disease population.31,32 It has recently been shown that a high depression score before transplantation (using the Beck Depression Inventory) was correlated to poor outcome.33 In our study, there was a significant relationship between pain and depression (P ¼ 0.01), and according to the multiple regression study, an increase of 10 points in the depression score leads to an average of 1.1 point increase in pain scores. This result also should be taken into account in our practice: depression should be systematically evaluated, treated by pharmacological or nonpharmacological therapies, and improvement must be followed up. Back pain was the pain most frequently experienced by our patients. Back pain is mostly of musculoskeletal origin and related to thoracic kyphosis in CF patients and postural abnormalities and osteoporosis in all the patients.34,35 Osteoporosis, which is mainly related to loss of body mass, inability to exercise, and frequent use of corticoids, may lead to compression fractures of thoracic and lumbar vertebrae.36 Fifty-eight percent of our patients with pain, or 44% of all our patients, reported difficulties in walking that impacted on their autonomy. However, only 19% of all patients underwent regular physical therapy and reconditioning. This rate is consistent with the poor participation of this population in daily physical activity.37
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Classically, headache is linked to sinusitis, nasal polyps in CF patients, or hypercapnia in end-stage lung disease. Chest pain could be muscular or related to pleural lesions, a broken rib, or pneumothorax and was frequently reported. Abdominal pain is related to distal intestinal obstruction syndrome, nonobservance of pancreatic extract treatment, or gastroesophageal reflux; it is known to occur more frequently in young CF patients. Our patients presented a low prevalence of abdominal pain compared with other CF studies with a high proportion of young people. Procedural pain was reported by only 7% of all patients. This prevalence is much lower than that in some other studies where it can be as high as 78%.10 Although we can stress the good quality of care for all the potentially painful procedures in our institution, some cases may have been missed as some procedures are performed at long intervals and patients were asked to report procedural pain for the last week. However, although pain mechanisms could be different in our groups of patients, we did not find any difference in pain location when we compared pain patients with CF with pain patients without CF. Only 39% of the patients reporting pain took analgesics. This is lower than the proportion found in other studies, where 50% to 68% of patients took analgesic drugs.9,10 Many patients, when asked why they did not take analgesic agents, answered that they did not find them efficient while having side effects; others did not want to add these drugs to an already long list of medications. Interestingly, Festini et al.9 had previously reported that among 225 CF patients who reported pain symptoms, 26% did nothing to fight the pain. Nonpharmacological approaches are difficult to analyze as techniques as different as homeopathy, transcutaneous electrical nerve stimulation, relaxation, or hypnosis could be reported by patients. Nevertheless, only 19% of our pain patients had at least one or more attempt at these approaches. Although this percentage is close to that reported by others,9,10 it is much lower than those of centers where pain patients are systematically referred to a pain treatment department and where noninvasive forms of pain control are more widely used and considered as first-line therapies.5 Alternative therapies also could be used for anxiety and depressive conditions, but only one of our patients reported relaxation therapy for relief of anxiety. Only two patients in our population reported use of opioids. Opioid use in this kind of population varies widely depending on country and hospital. In France, Sermet-Gaudelus et al.10 noted that of 89 adults with pain, only one patient took opioids, whereas a North American study reported that 53% of 78 patients with severe CF were taking opioids for pain.5 This difference could be the
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result of different risk appraisals for tolerance manifestations, postoperative hyperalgesia, or side effects such as constipation or respiratory impairment.38 This study has several limitations that must be considered. Patients were considered ‘‘with pain’’ if they answered ‘‘yes’’ to the question ‘‘Do you suffer regularly from pain?’’ Patients were also considered ‘‘with pain’’ if they answered ‘‘no’’ to the question but had a score greater than 3 on one or more of the three scales. The cutoff of >3 is usually considered to separate mild pain not requiring any systematic treatment from more severe pain requiring a systematic treatment. Although a physical examination was conducted by a pain-qualified anesthesiologist, it was most of the time difficult to identify the cause of pain. For example, dorsal pain, which is very frequent, could be the result of the association of kyphotic posture, vertebral wedging secondary to osteoporosis, and pleurisy, and also could be worsened by physiotherapy. Another limit of our study is that we did not ask the patient to indicate the percentage of relief provided by pain treatments or medications. Consequently, this could explain that some patients took analgesics less frequently than other patients because they were not satisfied.
Conclusion This study highlights the prevalence of pain in our patients and specific problems associated with pain such as anxiety and depression. Appropriate assessment and treatment of pain using pharmacological, psychological support, and/or complementary therapies must be considered a significant component of the management of these patients.
Disclosures and Acknowledgments This research was supported by a grant (TP0904) from the ‘‘Vaincre la Mucoviscidose’’ association. The funding source was not involved in the conduct of the study or development of the submission. The authors declare no conflicts of interest.
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