Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder caused by mutations
in the dystrophin gene, leading to the total absence of or an abnormal, but partly
functional, dystrophin protein[1],[2]. Duchenne muscular dystrophy is characterized by progressive muscle weakness, ambulation
loss and premature death[3]. The lack of dystrophin results in degeneration of muscle fibers, which are replaced
by fat and connective tissue[1]. Boys with DMD show an initial period of gain in motor skills, followed by a plateau
in acquisitions, which is then followed by a decline and ambulation loss[4].
Historically, pain has not been considered to be a major part of the symptom manifestation
of DMD. However, a growing number of studies indicate that chronic pain is a common
symptom for people with neuromuscular diseases (NMD)[1],[5],[6].
Chronic pain may be common, even though it is not the primary concern of patients
or doctors[7]. In some cases, pain can be the leading problem with adverse consequences on function
and quality of life. Pain is described as “an unpleasant sensory and emotional experience
that is associated with actual or potential tissue damage or described in such terms”.
Causes of pain in NMD are multifactorial, due to muscular overuse, severe contractures,
vertebral fractures (caused by osteoporosis) and/or orthopedic procedures[1],[5],[6].
Pain in NMD may be under-assessed and underestimated because of its nature and because
of the context of a disorder that affects mobility. Expression of pain complaint also
may be influenced by various psychological factors[7]. The pain perceived as related to NMD or therapeutic procedures may be denied or
seen as fate by both patient and caregiver. There are also causes that are difficult
to recognize and assess that represent a therapeutic problem. Such causes are a result
of fears of using certain substances in patients with a potential for cardiac or respiratory
risk[7].
Knowledge about pain in children and adolescents with DMD is limited in terms of frequency,
intensity, location, discomfort and the impact on function and quality of life. This
topic is important for treatment options and understanding the impact of pain on patient
compliance and the outcomes of other rehabilitation interventions[1]. Moreover, fatigue, pain, and affective disorders may encourage effective treatment
strategy planning by health care providers[2]. Therefore, this study aimed to investigate the relationship between DMD and pain.
METHODS
This review was based on a systematic search of published articles available in June,
2015. It was conducted according to the Preferred Reporting Items for Systematic Reviews
and Meta-Analyses (PRISMA) guidelines[8],[9].
The articles were searched for through Medline/PubMed and BVS (virtual library in
health) databases, with keywords that had to be in all fields. We included articles
that showed the terms: “Muscular Dystrophy, Duchenne” and “Pain”.
To select the articles, we used three steps ([Figure 1]). The first step consisted of searching for articles in databases and reading the
titles and abstracts. The second step was exclusion of studies by title, abstract,
and inclusion criteria analysis. Inclusion criteria included the investigation of
pain in patients with DMD as the main focus of the study and/or quantifying pain in
patients with DMD. The last step was an analysis of the full text of eligible works[10],[11].
Figure 1 Steps used in studies selection.
To increase confidence in article selection, two researchers reviewed all the potentially
relevant articles independently. After that, the researchers agreed which articles
fulfilled the inclusion criteria[10],[11],[12].
The abstracts of identified articles were screened for the following inclusion criteria
([Table 1]): (1) included a population with a diagnosis of DMD, and (2) pain assessment in
this population. There were no restrictions about minimum sample size. Articles were
excluded if they were: (1) not data-based (e.g. books, theoretical papers, or secondary
reviews), (2) not in English, (3) not performed with the populations identified as
having DMD diagnosis, or (4) not clearly focused on pain evaluation. We planned to
pool statistical data from quantitative studies within meta-analyses.
Table 1
Representation of the search strategy – PICOs criteria for the studies included.
|
PICO
|
Population: muscular dystrophy, Duchenne
|
|
Intervention: control or evaluation of pain
|
|
Comparator (control): interventions for pain control
|
|
Outcome: pain reported by patients or family members
|
|
Study design(s): clinical trials, case-control, cross-sectional, case reports and case series
|
All identified studies were collected in EndNote Web (Thomson Reuters) and duplicates
were removed.
DISCUSSION
According to the studies analyzed in this review, pain is a common and frequent problem
in individuals with DMD, associated with their physical limitations and general aspects
of the disease, vertebral fractures[13] and scoliosis[15]. The youths and adults with DMD experience significant problems with pain that negatively
affect their lives. Clinicians caring for these patients should investigate the nature
of pain and its extent[6]. Although pain is a common occurrence in boys with DMD, it may still be under-recognized[5].
All eight reviewed studies contained distinct participants and sample sizes. The largest
DMD population investigated was 80 patients[2]. The smallest population was in the Sbrocchi et al. study of seven DMD patients[13]. The number of participants in studies is important to adequately portray the population.
However, considering studies with disabled patients, most samples are by convenience[11].
Furthermore, Lager et al.[1] and Guy-Coichard et al.[7] presented data from DMD and Becker muscular dystrophy patients analyzed together
(n = 38 and 128, respectively). Engel et al.[6] analyzed patients with neuromuscular diseases in general. Bray et al. investigated
pain in DMD patients according to their parents’ reports[5].
A variety of instruments was used in the reviewed studies to qualify and quantify
pain. The most common instruments used in these studies were the Visual Analogue Scales
(VAS)[1],[5],[15] and the Brief Pain Inventory (BPI)[1],[6],[7]. Other important factors are pain frequency and duration. Some studies conducted
only an assessment of pain[1],[2],[5],[6],[7],[14]. Another three studies analyzed pain at different times: pre and post two years
of bisphosphonate therapy[13]; before surgery and after six weeks, one year, and two years[15]; and in six-month follow-ups[14].
As the studies mentioned above evaluated patients in different time scales, it was
possible to notice pain relief after differing interventions or periods of time, but
not to compare intervention protocols. Takaso et al.
[15] observed pain relief in DMD patients postsurgery and therapy, respectively. They
showed that all patients had back pain before surgery. Their patients reported that
the difficulty sitting and back pain were alleviated after surgery. The mean VAS improved
from 6.2 before surgery to 2.5, 1.8 and 1.6 after six weeks, one year and two years
after surgery, respectively. According to Sbrocchi et al.[13], three boys reported complete back pain resolution and the remaining reported significant
improvement at follow-up. Back pain improved in all patients within 30 days of bisphosphonate
therapy administration, and the two boys who developed incident fractures during treatment
did not report back pain[13]. The DMD bodily pain score remained the same after six months, in the Bray et al.[14] study, with no intervention.
Studies found in this review suggested that most of the boys with DMD present with
some level of pain. With interventions, such as surgery or drug administration, the
boys with DMD showed some improvement on pain reports, or even complete resolution,
making this a good approach to specific cases of pain. With no intervention, the pain
score remained the same.
Pain assessment differed between the included studies. Sbrocchi et al.[13] and Takaso et al.[15] observed back pain intensity. Pangalila et al.[2] and Bray et al.[14] observed bodily pain in general. Lager and Kroksmark,[1] Engel et al.[6], Zebracki and Drotar[5] and Guy-Coichard et al.,[7] analyzed pain in various aspects, which included symptoms, intensity, frequency,
duration, location, interference and factors exacerbating the impact of pain.
Highlighting pain frequency, duration and location, Zebracki and Drotar[5] observed the occurrence of pain three or fewer times a month with a duration less
than one hour. The pain was commonly in the lower back, spine, legs, and pelvic region
of DMD patients, and was described as continuous. Lager and Kroksmark[1] observed most of the adolescents with DMD/Becker muscular dystrophy (BMD) as having
weekly pain, lasting at least three months or more and a duration from one to 12 hours.
Guy-Coichard et al.[7] and Lager and Kroksmark[1] showed that most patients reported the occurrence of pain in the previous three
months. Lager and Kroksmark[1] also showed 41% of DMD/BMD patients reporting chronic pain and, in Pangalila et
al.[2], 65% of the subjects had had pain for longer than three months. Diffuse pain sites
were found in 36% of patients in the Guy-Coichard et al.[7] study. Lager’s and Kroksmark’s[1] results are similar to those of Zebracki and Drotar[5] with respect to the pain location. The most common body regions were neck/back and
legs, and in three to four different locations[1]. Pangalila et al.[2] found more than half of the DMD individuals had pain in more than one location such
as legs, arms, shoulders, and back, concluding that many complaints were musculoskeletal.
The influence of pain on other factors was also explored in the reviewed studies.
Zebracki and Drotar[5] showed little to moderate (47.8%) or not at all (39.1%) emotional upset due to pain
in children with DMD. Several daily activities were impacted by pain, including sitting,
sleeping, and riding in a car/bus according to reports by the DMD children[5]. In children with DMD, the experience of pain while engaging in common behaviours
may contribute to avoidance of those activities, which may lead to poor health behaviour,
social withdrawal and isolation, and impaired school/work functioning[5]. However, the impact of pain on the daily life of DMD/BMD patients was small in
the study by Guy-Coichard’s et al.[7]. General activities and mood were the areas most affected by pain, followed by mobility
and schoolwork. Sleep and relationships with others were the least affected[7].
The main factors perceived by DMD and BMD adolescents to exacerbate pain were sitting,
too much movement/activity and being lifted and transferred; some examples of other
factors exacerbating pain were driving the power wheelchair, lying in bed, especially
at night, and thinking about the pain[1]. The most common factors that were identified as relieving pain were resting, changing
position, massage and use of painkillers. Other factors for relieving pain were doing
something fun, and thinking about something else[1].
Most studies show that pain affects the daily activities of boys with DMD. However,
according to Pangalila et al.[2], the frequent occurrence of pain symptoms, very often chronic, is not reflected
in their associations with quality of life[2]. This is controversial and should be highlighted, considering that this is the study
with the largest sample size. However, these patients were older and, possibly, daily
life had already been compromised by the late stage of the disease. This may be a
pitfall as it may lead to the under diagnosis of pain, with patients possibly less
likely to mention it among their main complaints[2].
Individual factors must be considered in these results on pain in patients with DMD.
In Zebracki and Drotar’s[5] study, 69.8% of DMD patients received special services, 58.1% received physical
therapy and 46.5% received occupational therapy. All participants in the study by
Pangalila et al.[2] were dependent on mechanical ventilation, with 46% receiving non-invasive ventilation
and 53% receiving invasive ventilation. All these participants were also wheelchair
dependent, severely impaired in upper limb function and 25% used medication for pain
relief. Guy-Coichard et al.[7] observed that 70% of their patients were permanently wheelchair bound.
Pain reports on DMD patients by their parents showed DMD patients had a worse possible
health state than the general paediatric population, including bodily pain[14]. Children with DMD and their parents indicated significantly more intense pain than
the did physician, and children who complained of more severe pain were viewed by
parents as having poorer overall emotional functioning when compared with children
with low levels of pain intensity.
Youth and parent data on pain frequency, pain duration, and emotional distress due
to pain were not significantly different. Parents reported significantly more limitations
in activity than the children reported, and the parents reported more intense pain
than the patients[5].
The assessments used in the study by Lager and Kroksmark allow an understanding of
the nature of pain, its scope and impact on everyday life[1]. They emphasize the necessity of assessing pain in a systematic manner in this population.
The heterogeneity of factors perceived to exacerbate and relieve pain, as well as
the consequences in everyday life, highlight the importance of an individual approach
to interventions designed to reduce pain[1].
Multidimensional assessments can support clinical management by improving current
treatment strategies targeted toward fatigue and pain[2]. According to Pangalila et al.[2], fatigue, pain, anxiety, and depression occur frequently in adults with DMD, often
concurrently, and may be underdiagnosed. Pain is more frequent in those with a poor
quality of life, but still has a high prevalence in the group of adults with DMD who
report good quality of life. Fatigue, pain and depression are more common in those
with a poor quality of life. Effective diagnosis and subsequent treatment could alleviate
the disease burden of DMD in adult men[2].
Due to the progressive nature of DMD, the needs and functionality of children will
change over time and should be documented in a prospective study. A longitudinal study
would also help to determine causal relationships between variables[5].
According Lager and Kroksmark[1], further studies are required to examine the treatment efficacy of cognitive and
behavioral interventions to improve the ability of adolescents to cope with, and reduce
the impact of, pain. Knowledge of pain and activity limitations can be used to identify
problems and barriers faced by these children and to develop interventions that target
these areas[16].
As Guy-Coichard et al.
[7] showed in their study, vertical position, maintaining a fixed position and changes
in position, and physical exercise can worsen pain. This knowledge is important, as
patients can use tools such as massage, physiotherapy or local heat applications to
relieve pain.
Pharmacological options may be beneficial in reducing pain symptoms and, consequently,
reducing activity limitations in children with DMD. In addition, cognitive-behavioral
treatments designed to improve children’s ability to manage and cope with pain may
help to minimize the impact of pain on daily life[5].
Multimodal treatment for pain in DMD patients is necessary and involves pharmaceutical,
surgical, physical rehabilitation and psychosocial interventions. Future studies must
analyze pain longitudinally and systematically. Longitudinal studies will help determine
the causal relationships between variables. Aspects that exacerbate and relieve pain
and pain consequences in daily life activities in patients with DMD must be understood
in order to develop interventions to relieve pain.
