Indications for transplantation and medication among the 117 included lung recipients are shown in Table 2. The mean age of the pain free recipients was 53 years (SD 13.5) (range 22-70 years). Of the 113 recipients who answered all three instruments, 74 (65.5 %) reported pain, 40 women and 34 men with a mean age of 53 years (SD 12) (range 18-74 years). In the pain group, 71.6 % of the recipients were over the age of 50 years. In the group of patients younger than 50 years the prevalence of pain was 64.6 %, thus there was no significant difference between the two age groups. None of the patients were enrolled in a rehabilitation program at the time of their yearly follow-up

The prevalence of pain was 51% after 1 yr., 68 % after 2 yrs., 69.5 % after 3 yrs., 75 % after 4 yrs., and 54.5 % after 5 yrs. The proportion of recipients with pain did not differ between those on or not on CNIs (e.g., rapamycin).

The three most common pain locations were the chest, back, and legs (Table 3). Each recipient could report more than one pain location (range 1-7 pain locations). The pain most commonly started during the first hospital stay when the lung transplantation was performed or soon after discharge (32%). Among the patients with pain, 27 % developed chronic pain later than one year post transplantation, while 19 % already had pain pre-transplant. Finally, 0.5 % reported that they pain started in conjunction with a new disease and 21.5 % didn’t answer this particular question.

Regarding the sensory aspect, the most common pain sensation was dull followed by stabbing or burning (Table 4). The three most common affective experiences of pain were annoying, troublesome, and tiring (Table 5). The pain experience affected everyday life in various ways with the most commonly reported consequence being inability to plan or perform the daily occupation. The lung recipients with pain reported 13 different personal pain explanation models, the two most common being that they did not know why they had pain, and that the pain was caused by nerve injuries (Table 6).

The pain intensity measured by the POM-VAS ranged from 0-28 cm, and a total VAS score was calculated for each lung recipient. The median POM-VAS was 4 cm (P₂₅=0; P₇₅= 9). The sensory and affective scores were added together to form a total pain intensity score (PIS) for POM-WDS, which ranged from 0-112. The median PIS was 12 (P ₂₅=0; P₇₅=28).

Lung recipients with pain experienced significantly lower psychological general well-being (PGWB) (p=0.021), more anxiety (p=0.047), more depression (p=0.003), and poorer general health (p<0.001) compared to lung recipients without pain. The lung recipients with pain also reported significantly lower self-efficacy (p=0.004).

Linear regression analysis revealed a significant relationship between overall PGWB and Pain Intensity Score (PIS) (Beta -0.481), where the overall PGWB contributes significantly to pain intensity (p=0.005). The overall PGWB seems to explain 21.6 % of the variance of PIS (R Square 0.216). There was also a significant relationship between self-efficacy and PIS (Beta -0.402) where self-efficacy contributes significantly to pain intensity (p≤0.001). Self-efficacy appears to explain 16.2 % of the variance of PIS (R Square 0.162). Thus PGWB seems to be a better predictor of the total PIS than low self-efficacy.

There were no significant differences in the proportions of men and women with pain. Of the participants with pain, 54.1 % were women and 45.9 % men. Among the women, 74.1 % reported pain compared to 59.6% of the men. There were significant differences between male and female lung recipients regarding POM-VAS (p=.010), POM-WDS (p=.015) and PIS (p=.006), where women experienced higher pain intensity as well as worse sensory and affective burden. Female recipients had 1.5 higher odds of experiencing pain when adjusted for PGWB, which was not significant (OR 1.503, 95 % CI 0.666-3.391). PGWB contributed significantly (p=0.028) to the prevalence of pain. Thus, the major factor contributing to lung recipients’ pain is the overall psychological general well-being adjusted for gender. The higher the PGWB, the lower the odds of experiencing pain (OR 0.973, 95 % CI 0.950-0.977) when adjusted for gender. The analysis also showed that when perceived self-efficacy increases, the probability of experiencing pain is significantly (p=0.010) reduced (OR 0.747, 95 % CI 0.598 – 0.933).

The key findings in this study are:

·Chronic pain is very common in the first five years after lung transplantation ranging from 54.5-75 % of lung recipients.

·The most common pain locations are the chest, back, and legs.

·The pain reduces psychological general well-being and self-efficacy.

·Female lung recipients report higher pain intensity and worse sensory and affective burden than male lung recipients.

Chronic pain was more common than we could possibly have imagined. Moderate to severe persistent postsurgical pain occurred in 5-10 % of the patients in a Danish nationwide study of chronic pain after lung transplantation 28, which in turn was lower than that reported after non-transplant thoracotomy. The self-rated prevalence of generalized pain in the general Swedish population is 10-15 % 2930. In total, 24 % of the population is living with persistent pain, i.e., lasting for more than 3 months, with an increased risk of various co-morbidities 31. For example, among persons with chronic pain the lifetime prevalence of depression is 58-86 % and anxiety 35-62 % 32. In the Regional database of care consumption in the south of Sweden about 3 % of the population is diagnosed with generalized pain each year. While such pain might be viewed as a specificdisease per se, pain is also a common symptom of many other diseases including chronic conditions 33. Thus, the prevalence of pain among lung recipients is far above that of the general population, which constitutes an important aspect of long-term management after lung transplantation.

We did not explore the cause of the pain. However, the pain locations suggest multiple causes such as the incision, CIPS (especially pain in the hands, feet, joints, and head), and the side-effects of immunosuppressive drugs other than CNIs. The chest pain may be due to post thoracotomy pain syndrome (PTPS) that may have an incidence of more than 50 % 34 and be related to intra operative factors such as whether anterolateral thoracotomy or classic posterolateral thoracotomy was applied. The apparent etiology of PTPS is nerve damage and loss of superficial abdominal reflexes 34, thus it is noteworthy that in ten cases the personal models for explaining the pain involved nerve injury. None of these factors were explored in the present study, but will be analyzed in an ongoing prospective study. Due to the sensory descriptions in at least hands and feet it is reasonable to believe that we partly deal with neuropathic pain. For some time it has been recognized that inflammatory mediators released from immune cells can contribute several persistent pain states. Immune cell products might have a crucial role not just in inflammatory pain but also in neuropathic pain caused by damage to peripheral nerves or to the CNS 35. Accumulating evidence suggests that non-neuronal cells such as immune cells, glial cells, keratinocytes, cancer cells and stem cells play active roles in the pathogenesis and resolution of pain. Recent studies also suggest that bacterial infections regulate pain through direct actions on sensory neurons, and specific receptors are present in nociceptors to detect danger signals from infections 36. Since all the lung recipients were treated with CNIs more than one year our understanding is that the immunological condition caused by the anti-rejection treatment might be one reason behind the high prevalence of pain along with the occurrence of bacterial infections.

The findings reveal that 18 recipients experienced no consequences in their everyday life, suggesting that it is possible to experience pain and still mange one s daily occupation without limitations. However, in a majority of cases chronic pain affects everyday life, which is supported by the Danish survey 28 where daily social activities were limited in 29-92 % of the participants and where more than half of the LuTx felt that their QoL was compromised due to pain. The consequences regarding HRQoL from our data are currently being analyzed and will be reported later.

In our study PGWB was reduced, but we do not know whether pain causes anxiety, depression, and poor general health or if reduced PGWB increases the experience of pain. The design does not permit any suggestions or conclusions regarding cause-effect. One concern is that self-efficacy was impaired among LuTX with pain. The ability to achieve certain goals is important for the experience of health and as self-efficacy is a pre-condition for self-management 37, the latter might also be limited by chronic pain. We argue that chronic pain after lung transplantation might hamper the recipient s ability to manage the symptoms, treatment, physical and psychosocial consequences, and life style changes inherent in living with the chronic condition of being a lung recipient.

As recommended in the consensus report on gender differences in pain and analgesia 38, we tested the pain experience in both sexes. Women with pain experienced significantly higher pain intensity and pain related illness than men with pain. Despite the lack of evidence, our understanding is that the differences in experienced pain intensity refer more to societal based gender phenomena than purely biological sex differences. The gender role might differ for female lung recipients and our findings suggest that both PGWB and self-efficacy affect the pain experience. It is well-established that there is a 2 to 6 fold greater prevalence and intensity of chronic pain syndromes in women compared to men 38. As women are more likely than men to have a history of clinical pain experiences and pain history influences pain perception, we argue that pre-transplant multi-dimensional pain assessment should be mandatory for all transplant candidates, but especially for female lung transplant candidates.