J Yeungnam Med Sci.  2022 Jul;39(3):181-189. 10.12701/jyms.2022.00332.

Pain in amyotrophic lateral sclerosis: a narrative review

• Kwak S

• KMID: 2532070
• DOI: http://doi.org/10.12701/jyms.2022.00332

Abstract

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative condition characterized by loss of motor neurons, resulting in motor weakness of the limbs and/or bulbar muscles. Pain is a prevalent but neglected symptom of ALS, and it has a significant negative impact on the quality of life of patients and their caregivers. This review outlines the epidemiology, clinical characteristics, underlying mechanisms, and management strategies of pain in ALS to improve clinical practice and patient outcomes related to pain. Pain is a prevalent symptom among patients with ALS, with a variable reported prevalence. It may occur at any stage of the disease and can involve any part of the body without a specific pattern. Primary pain includes neuropathic pain and pain from spasticity or cramps, while secondary pain is mainly nociceptive, occurring with the progression of muscle weakness and atrophy, prolonged immobility causing degenerative changes in joints and connective tissue, and long-term home mechanical ventilation. Prior to treatment, the exact patterns and causes of pain must first be identified, and the treatment should be tailored to each patient. Treatment options can be classified into pharmacological treatments, including nonsteroidal anti-inflammatory drugs, antiepileptic drugs, drugs for cramps or spasticity, and opioid; and nonpharmacological treatments, including positioning, splints, joint injections, and physical therapy. The development of standardized and specific assessment tools for pain-specific to ALS is required, as are further studies on treatments to reduce pain, diminish suffering, and improve the quality of life of patients with ALS.

Keyword

Amyotrophic lateral sclerosis; Motor neuron disease; Non-motor symptoms; Pain; Palliative care

Figure

• 

  Fig. 1. Types of pain in amyotrophic lateral sclerosis. Most reported types of pain are secondary in nature (mainly nociceptive; blue shading), but there is some evidence for primary forms of pain (green shading), such as neuropathic pain, spasticity, and cramps. NIV, noninvasive ventilation. Reprinted from Chiò et al. [26] with permission from Elsevier.

Reference

References

1. Kiernan MC, Vucic S, Cheah BC, Turner MR, Eisen A, Hardiman O, et al. Amyotrophic lateral sclerosis. Lancet. 2011; 377:942–55.

2. Brooks BR. El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. J Neurol Sci. 1994; 124(Suppl):96–107.

3. Brooks BR, Miller RG, Swash M, Munsat TL; World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron Disord. 2000; 1:293–9.

4. de Carvalho M, Dengler R, Eisen A, England JD, Kaji R, Kimura J, et al. Electrodiagnostic criteria for diagnosis of ALS. Clin Neurophysiol. 2008; 119:497–503.

5. Turner M, Jenkins L. Defining the syndrome. In : Turner M, Jenkins L, editors. Diagnosing amyotrophic lateral sclerosis: clinical wisdom to facilitate faster diagnosis. Oxford: S. Karger Publishers Limited;2020. p. 7–24.

6. Mahoney CJ, Ahmed RM, Huynh W, Tu S, Rohrer JD, Bedlack RS, et al. Pathophysiology and treatment of non-motor dysfunction in amyotrophic lateral sclerosis. CNS Drugs. 2021; 35:483–505.

7. Renton AE, Majounie E, Waite A, Simón-Sánchez J, Rollinson S, Gibbs JR, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. 2011; 72:257–68.

8. Burrell JR, Kiernan MC, Vucic S, Hodges JR. Motor neuron dysfunction in frontotemporal dementia. Brain. 2011; 134(Pt 9):2582–94.

9. Drake ME Jr. Chronic pain syndrome in amyotrophic lateral sclerosis. Arch Neurol. 1983; 40:453–4.

10. de Castro-Costa CM, Oriá RB, Machado-Filho JA, Franco MT, Diniz DL, Giffoni SD, et al. Amyotrophic lateral sclerosis: clinical analysis of 78 cases from Fortaleza (northeastern Brazil). Arq Neuropsiquiatr. 1999; 57(3B):761–74.

11. Ganzini L, Johnston WS, Hoffman WF. Correlates of suffering in amyotrophic lateral sclerosis. Neurology. 1999; 52:1434–40.

12. Åkerblom Y, Jakobsson Larsson B, Zetterberg L, Åsenlöf P. The multiple faces of pain in motor neuron disease: a qualitative study to inform pain assessment and pain management. Disabil Rehabil. 2020; 42:2123–32.

13. Chiò A, Canosa A, Gallo S, Moglia C, Ilardi A, Cammarosano S, et al. Pain in amyotrophic lateral sclerosis: a population-based controlled study. Eur J Neurol. 2012; 19:551–5.

14. Raheja D, Stephens HE, Lehman E, Walsh S, Yang C, Simmons Z. Patient-reported problematic symptoms in an ALS treatment trial. Amyotroph Lateral Scler Frontotemporal Degener. 2016; 17:198–205.

15. Wallace VC, Ellis CM, Burman R, Knights C, Shaw CE, Al-Chalabi A. The evaluation of pain in amyotrophic lateral sclerosis: a case controlled observational study. Amyotroph Lateral Scler Frontotemporal Degener. 2014; 15:520–7.

16. EFNS Task Force on Diagnosis and Management of Amyotrophic Lateral Sclerosis, Andersen PM, Abrahams S, Borasio GD, de Carvalho M, Chio A, et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS): revised report of an EFNS task force. Eur J Neurol. 2012; 19:360–75.

17. Miller RG, Jackson CE, Kasarskis EJ, England JD, Forshew D, Johnston W, et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: multidisciplinary care, symptom management, and cognitive/behavioral impairment (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology. 2009; 73:1227–33.

18. Brettschneider J, Kurent J, Ludolph A. Drug therapy for pain in amyotrophic lateral sclerosis or motor neuron disease. Cochrane Database Syst Rev. 2013; 2013:CD005226.

19. Stephens HE, Lehman E, Raheja D, Yang C, Walsh S, Mcarthur DB, et al. Pain in amyotrophic lateral sclerosis: patient and physician perspectives and practices. Amyotroph Lateral Scler Frontotemporal Degener. 2015; 17:21–9.

20. Truini A, Biasiotta A, Onesti E, Di Stefano G, Ceccanti M, La Cesa S, et al. Small-fibre neuropathy related to bulbar and spinal-onset in patients with ALS. J Neurol. 2015; 262:1014–8.

21. Dalla Bella E, Lombardi R, Porretta-Serapiglia C, Ciano C, Gellera C, Pensato V, et al. Amyotrophic lateral sclerosis causes small fiber pathology. Eur J Neurol. 2016; 23:416–20.

22. Hanisch F, Skudlarek A, Berndt J, Kornhuber ME. Characteristics of pain in amyotrophic lateral sclerosis. Brain Behav. 2015; 5:e00296.

23. Pizzimenti A, Aragona M, Onesti E, Inghilleri M. Depression, pain and quality of life in patients with amyotrophic lateral sclerosis: a cross-sectional study. Funct Neurol. 2013; 28:115–9.

24. Jensen MP, Abresch RT, Carter GT, McDonald CM. Chronic pain in persons with neuromuscular disease. Arch Phys Med Rehabil. 2005; 86:1155–63.

25. Hurwitz N, Radakovic R, Boyce E, Peryer G. Prevalence of pain in amyotrophic lateral sclerosis: a systematic review and meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. 2021; 22:449–58.

26. Chiò A, Mora G, Lauria G. Pain in amyotrophic lateral sclerosis. Lancet Neurol. 2017; 16:144–57.

27. Borasio GD, Voltz R, Miller RG. Palliative care in amyotrophic lateral sclerosis. Neurol Clin. 2001; 19:829–47.

28. Moisset X, Cornut-Chauvinc C, Clavelou P, Pereira B, Dallel R, Guy N. Is there pain with neuropathic characteristics in patients with amyotrophic lateral sclerosis?: a cross-sectional study. Palliat Med. 2016; 30:486–94.

29. Lopes LC, Galhardoni R, Silva V, Jorge FM, Yeng LT, Callegaro D, et al. Beyond weakness: Characterization of pain, sensory profile and conditioned pain modulation in patients with motor neuron disease: a controlled study. Eur J Pain. 2018; 22:72–83.

30. An R, Li Y, He X, Li C, Li X, Xu Y, et al. The evaluation of pain with nociceptive and neuropathic characteristics from three different perspectives in amyotrophic lateral sclerosis patients: a case controlled observational study in Southwestern China. Neural Plast. 2021; 2021:5537892.

31. van Hecke O, Austin SK, Khan RA, Smith BH, Torrance N. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014; 155:654–62.

32. Taga A, Schito P, Trapasso MC, Zinno L, Pavesi G. Pain at the onset of amyotrophic lateral sclerosis: a cross-sectional study. Clin Neurol Neurosurg. 2019; 186:105540.

33. Miller RG, Mitchell JD, Moore DH. Riluzole for amyotrophic lateral sclerosis (ALS)/motor neuron disease (MND). Cochrane Database Syst Rev. 2012; 2012:CD001447.

34. Moon ES, Karadimas SK, Yu WR, Austin JW, Fehlings MG. Riluzole attenuates neuropathic pain and enhances functional recovery in a rodent model of cervical spondylotic myelopathy. Neurobiol Dis. 2014; 62:394–406.

35. Poupon L, Lamoine S, Pereira V, Barriere DA, Lolignier S, Giraudet F, et al. Targeting the TREK-1 potassium channel via riluzole to eliminate the neuropathic and depressive-like effects of oxaliplatin. Neuropharmacology. 2018; 140:43–61.

36. Palese F, Sartori A, Logroscino G, Pisa FE. Predictors of diagnostic delay in amyotrophic lateral sclerosis: a cohort study based on administrative and electronic medical records data. Amyotroph Lateral Scler Frontotemporal Degener. 2019; 20:176–85.

37. Galvin M, Ryan P, Maguire S, Heverin M, Madden C, Vajda A, et al. The path to specialist multidisciplinary care in amyotrophic lateral sclerosis: a population- based study of consultations, interventions and costs. PLoS One. 2017; 12:e0179796.

38. Paganoni S, Macklin EA, Lee A, Murphy A, Chang J, Zipf A, et al. Diagnostic timelines and delays in diagnosing amyotrophic lateral sclerosis (ALS). Amyotroph Lateral Scler Frontotemporal Degener. 2014; 15:453–6.

39. Belsh JM, Schiffman PL. Misdiagnosis in patients with amyotrophic lateral sclerosis. Arch Intern Med. 1990; 150:2301–5.

40. Chiò A. ISIS Survey: an international study on the diagnostic process and its implications in amyotrophic lateral sclerosis. J Neurol. 1999; 246(Suppl 3):III1–5.

41. Cellura E, Spataro R, Taiello AC, La Bella V. Factors affecting the diagnostic delay in amyotrophic lateral sclerosis. Clin Neurol Neurosurg. 2012; 114:550–4.

42. Househam E, Swash M. Diagnostic delay in amyotrophic lateral sclerosis: what scope for improvement? J Neurol Sci. 2000; 180:76–81.

43. Miller TM, Layzer RB. Muscle cramps. Muscle Nerve. 2005; 32:431–42.

44. Swash M, Czesnik D, de Carvalho M. Muscular cramp: causes and management. Eur J Neurol. 2019; 26:214–21.

45. Caress JB, Ciarlone SL, Sullivan EA, Griffin LP, Cartwright MS. Natural history of muscle cramps in amyotrophic lateral sclerosis. Muscle Nerve. 2016; 53:513–7.

46. Mayer NH. Clinicophysiologic concepts of spasticity and motor dysfunction in adults with an upper motoneuron lesion. Muscle Nerve Suppl. 1997; 6:S1–13.

47. Verschueren A, Grapperon AM, Delmont E, Attarian S. Prevalence of spasticity and spasticity-related pain among patients with amyotrophic lateral sclerosis. Rev Neurol (Paris). 2021; 177:694–8.

48. Smart KM, Blake C, Staines A, Doody C. Clinical indicators of ‘nociceptive’, ‘peripheral neuropathic’ and ‘central’ mechanisms of musculoskeletal pain: a Delphi survey of expert clinicians. Man Ther. 2010; 15:80–7.

49. Borasio GD, Shaw PJ, Hardiman O, Ludolph AC, Sales Luis ML, Silani V, et al. Standards of palliative care for patients with amyotrophic lateral sclerosis: results of a European survey. Amyotroph Lateral Scler Other Motor Neuron Disord. 2001; 2:159–64.

50. Ho DT, Ruthazer R, Russell JA. Shoulder pain in amyotrophic lateral sclerosis. J Clin Neuromuscul Dis. 2011; 13:53–5.

51. Hayashi T, Narita Y, Okugawa N, Hamaguchi E, Shibahara M, Kuzuhara S. Pressure ulcers in ALS patients on admission at a university hospital in Japan. Amyotroph Lateral Scler. 2007; 8:310–3.

52. Hirano YM, Yamazaki Y, Shimizu J, Togari T, Bryce TJ. Ventilator dependence and expressions of need: a study of patients with amyotrophic lateral sclerosis in Japan. Soc Sci Med. 2006; 62:1403–13.

53. Rivera I, Ajroud-Driss S, Casey P, Heller S, Allen J, Siddique T, et al. Prevalence and characteristics of pain in early and late stages of ALS. Amyotroph Lateral Scler Frontotemporal Degener. 2013; 14:369–72.

54. Wigand B, Schlichte I, Schreiber S, Heitmann J, Meyer T, Dengler R, et al. Characteristics of pain and the burden it causes in patients with amyotrophic lateral sclerosis: a longitudinal study. Amyotroph Lateral Scler Frontotemporal Degener. 2022; 23:284–91.

55. Isaacs JD, Dean AF, Shaw CE, Al-Chalabi A, Mills KR, Leigh PN. Amyotrophic lateral sclerosis with sensory neuropathy: part of a multisystem disorder? J Neurol Neurosurg Psychiatry. 2007; 78:750–3.

56. D’Ovidio F, d’Errico A, Farina E, Calvo A, Costa G, Chiò A. Amyotrophic lateral sclerosis incidence and previous prescriptions of drugs for the nervous system. Neuroepidemiology. 2016; 47:59–66.

57. Adelman EE, Albert SM, Rabkin JG, Del Bene ML, Tider T, O’Sullivan I. Disparities in perceptions of distress and burden in ALS patients and family caregivers. Neurology. 2004; 62:1766–70.

58. Pagnini F, Lunetta C, Banfi P, Rossi G, Fossati F, Marconi A, et al. Pain in amyotrophic lateral sclerosis: a psychological perspective. Neurol Sci. 2012; 33:1193–6.

59. National Institute for Health and Care Excellence (NICE). NICE guideline. Motor neuron disease: assessment and management [Internet]. London: NICE;2016. [cited 2022 May 8]. https://www.nice.org.uk/guidance/ng42.

60. Ng L, Khan F, Young CA, Galea M. Symptomatic treatments for amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst Rev. 2017; 1:CD011776.

61. Cruccu G, Truini A. A review of neuropathic pain: from guidelines to clinical practice. Pain Ther. 2017; 6(Suppl 1):35–42.

62. Oliver D. Opioid medication in the palliative care of motor neurone disease. Palliat Med. 1998; 12:113–5.

63. Baldinger R, Katzberg HD, Weber M. Treatment for cramps in amyotrophic lateral sclerosis/motor neuron disease. Cochrane Database Syst R. 2012; (4):CD004157.

64. Bello-Haas VD. Physical therapy for individuals with amyotrophic lateral sclerosis: current insights. Degener Neurol Neuromuscul Dis. 2018; 8:45–54.

65. Majmudar S, Wu J, Paganoni S. Rehabilitation in amyotrophic lateral sclerosis: why it matters. Muscle Nerve. 2014; 50:4–13.

66. McClelland S 3rd, Bethoux FA, Boulis NM, Sutliff MH, Stough DK, Schwetz KM, et al. Intrathecal baclofen for spasticity-related pain in amyotrophic lateral sclerosis: efficacy and factors associated with pain relief. Muscle Nerve. 2008; 37:396–8.

67. Yang J, Bauer BA, Wahner-Roedler DL, Chon TY, Xiao L. The modified WHO analgesic ladder: is it appropriate for chronic non-cancer pain? J Pain Res. 2020; 13:411–7.

68. Anekar AA, Cascella M. WHO analgesic ladder. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing;2022. [cited 2022 May 10]. https://www.ncbi.nlm.nih.gov/books/NBK554435/.