Pain in amyotrophic lateral sclerosis

doi:10.1016/S1474-4422(16)30358-1

The Lancet Neurology

Volume 16, Issue 2, February 2017, Pages 144-157

https://doi.org/10.1016/S1474-4422(16)30358-1 Get rights and content

Summary

Pain is a largely neglected symptom in patients with amyotrophic lateral sclerosis (ALS) although it is reported by most of these patients. It occurs at all stages of the disease and can be an onset symptom preceding motor dysfunction. Pain is correlated with a deterioration in patients' quality of life and increased prevalence of depression. In the later stages of ALS, pain can be severe enough to require increased use of sedative and analgesic drugs, and is among the events that predict clinical deterioration and death. The site of pain depends on the pain type or underlying mechanism (eg, painful cramps, nociceptive pain, or neuropathic pain). Given the multifactorial nature of pain in patients with ALS, different treatments have been suggested, ranging from non-steroidal anti-inflammatory drugs, drugs for neuropathic pain, opioids, and cannabinoids, to physical therapy strategies and preventive assistive devices. Further understanding of the pathophysiology is crucial to drive assessment in clinical trials of therapeutic strategies targeted at specific mechanisms and studies of individualised therapies.

Introduction

Amyotrophic lateral sclerosis (ALS) is a rare neurodegenerative disease with a fatal outcome, typically within 2–4 years from onset.¹ The ALS degenerative process involves upper and lower motor neurons with onset usually at the bulbar or spinal levels, causing progressive loss of limb strength, dysphagia, dysarthria, and respiratory failure. Motor neuron degeneration is the predominant cause of disability in patients throughout all stages of ALS and is eventually the cause of death. However, many patients also have involvement of extramotor components, particularly the prefrontal cortex, associated with cognitive impairment or frontotemporal dementia.2, 3 Although CNS sensory structures are generally not implicated, some evidence for sensory system involvement comes from neuropathological,4, 5 imaging,6, 7 and clinical5, 8, 9 studies, as well as from rodent models of ALS.10, 11

Pain was a mainly neglected symptom in ALS until about 10 years ago,¹² owing to a misconception of ALS as purely a motor disease, which led to clinicians not asking their patients about pain,12, 13 as has also been the case for other non-motor symptoms. However, in the past decade, the variability of ALS between affected individuals has clearly emerged, and among the wide range of neurological defects and adjunctive manifestations that have been investigated, several studies have focused on pain in ALS,13, 14, 15, 16, 17, 18 confirming earlier observations.19, 20, 21 Furthermore, pain in ALS has been considered, mostly from a therapeutic point of view, in the main guidelines on ALS treatment,22, 23 and has also been assessed in a Cochrane review.²⁴ Nevertheless, the incidence, severity, distribution, underlying mechanisms, and treatment of pain in ALS have not been completely addressed, mainly because of the absence of a standardised method for diagnosing pain, the scarcity of data on pain determinants, and confounding variables.

The importance of identification and assessment of pain in patients with ALS cannot be overlooked. Pain has profound detrimental effects on the quality of life of patients with ALS and their caregivers,14, 18, 25 and initial indications suggest that it could have prognostic significance.26, 27 Different types of pain might arise from different underlying mechanisms—eg, primary causes of pain, such as neuropathic pain, could arise from the impairment of somatosensory pathways, whereas secondary causes of pain, due to the effects of tissue damage, are mainly nociceptive—and understanding the pathophysiology of pain in ALS would be relevant to determine the best treatments for individual patients.

In this Review, we summarise the current understanding of pain in patients with ALS and explore potential directions for future research. We briefly describe the epidemiology of pain in patients with ALS, before outlining the key clinical characteristics, including the association between pain and other comorbidities. We also discuss potential underlying mechanisms, with assessment of the evidence for neuropathic, nociceptive, and central sensitisation origins of pain for this disease. Finally, we review existing management strategies and emphasise the need for more rigorous studies of treatments for pain in patients with ALS.

Section snippets

Epidemiology of pain in ALS

There are few systematic studies on pain in patients with ALS and only three longitudinal studies (appendix p 2). The reported frequency of pain in ALS varies greatly, from less than 15%20, 28, 29 up to 85%.14, 17, 25, 30, 31, 32, 33 This large variability can be explained by the different study designs and settings, and the different instruments used to identify and measure pain. Moreover, the number of patients with ALS included in these studies is often small (study numbers range from seven³³

Assessment of pain in the clinical setting

Despite the high frequency of pain in ALS and its negative effect on patients' quality of life, both the Practice Parameters of the American Academy of Neurology²² and the European Guidelines on the Clinical Management of ALS²³ discuss its treatment for patients with ALS but do not suggest proactive screening of this symptom during the course of the disease. In the results of an online survey of ALS clinics in the USA, in which only a third of physicians responded,³⁷ 92% stated that pain was

Characteristics of pain in ALS

In patients with ALS, great variability exists in the clinical manifestations and localisation of pain (figure), which depend on whether the pain represents primary mechanisms or results from the secondary effects of motor degeneration. Pain severity and the presence and nature of pain over the disease course also vary between individuals, and in some cases pain is evident before the presence of motor symptoms. Pain in ALS can be acute or chronic (when continuous for 3 months or longer). In

Mechanisms of pain in ALS

In patients with ALS, the association between the unpleasant sensory and emotional experiences that pain entails and the progressive degeneration of upper and lower motor neuron degeneration along with the involvement of other nervous system structures is poorly understood. According to the cross-sectional studies discussed above, much of the chronic pain experienced by patients with ALS seems to occur as a result of the motor impairment in ALS; however, secondary pain does not seem to explain

Treatment of pain in ALS

The ultimate need of patients with ALS experiencing pain is to reduce pain intensity and, if possible, prevent it from becoming chronic. After the cause of pain has been defined, the appropriate treatments, including pharmacological and non-pharmacological interventions, should be adopted, following guidelines when available, with the aim of providing patients with personalised therapies. Pharmacological treatments (table 1) are the main approaches for neuropathic and other types of primary

Conclusions and future perspectives

Patients with ALS can experience pain as a result of various causes including reduced mobility, cramps, and spasticity. On the basis of the available published work, pain should be considered as a condition that: (1) can complicate the course of ALS in a proportion of patients that varies according to the definition of pain used and the analysis, or not, of mood comorbidities; (2) can occur throughout the course of the disease; (3) commonly has a mild intensity, with the possible exception of

Search strategy and selection criteria

We searched PubMed (from 1966 to Oct 25, 2016), Embase (from 1980 to Oct 25, 2016), and the Cochrane Library (April, 1996, to Oct 25, 2016) for relevant titles using the terms “amyotrophic lateral sclerosis”, “motor neuron disease”, or “primary lateral sclerosis” in combination with “pain”, “sensory symptoms”, “cramps”, “pain therapy”, and “opioids”. Further material was gathered from reference lists, review articles, and major textbook chapters. We also included abstracts and reports from

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