Is pain part of a systemic syndrome in head and neck cancer?

  • Paolo BossiEmail author
  • Massimo Ghiani
  • Angela Argenone
  • Roberta Depenni
Review Article


Head and neck cancers (HNC) represent 5% of all malignancies worldwide with about 180,000 cancer deaths per year. Patients with HNC are characterized by a systemic inflammatory state, generally associated with worse outcomes. Treatment-related toxicity is common among HNC patients and causes systemic consequences such as fatigue or cognitive dysfunction. The therapeutic treatments of HNC involve the release in circulation of inflammatory systemic mediators, whose effects trigger a vicious circle that may lead to functional and behavioral alterations. The areas of the head and neck are highly sensitive to pain. Literature data confirm that in HNC patients, pain is one of the most distressing symptoms across all the phases of treatment. Pain is associated with worse general conditions, depression, fatigue, impaired cognitive functions, and lower survival rate. The treatment of advanced HNC cases is multimodal and requires a multidisciplinary psycho-socio-pharmacological approach mediated by a team of experts. The pharmacological approach in management of HNC patients with pain is fundamental and involves the use of opioids, NSAIDs, steroids, or other drugs. Opioids in pain management therapy in patients with HNC could allow the pain level to be adequately monitored, thus improving quality of life. The integration of opioid and non-opioid therapy as well as non-pharmacological interventions is essential for the rehabilitation of physical, social, and psychological functions and to achieve pain control in patients with HNC. Opioid treatment is the mainstay for pain control, being used both for background and breakthrough cancer pain (BTcP) episodes. Fentanyl, easily absorbed and generally well tolerated, appears to be a possible choice due to its versatility. Non-pharmacological interventions, such as tailored yoga, physical exercise, and acupuncture, may have a role in pain management in patients with HNC.


Head and neck cancer Pain Pain management Multidisciplinary approach Opioids 



The authors acknowledge Annarita Chieti, PhD, of Sanitanova S.r.l., who is responsible for the medical writing and editorial assistance.

Compliance with ethical standards

Conflict of interest

Paolo Bossi is a part of advisory boards of/consultant for Angelini, Roche, Merck, Kyowa Kirin, Astrazeneca, MSD, BMS, SunPharma, and Sanofi. Other authors have nothing to declare.


  1. 1.
    Green CR, Hart-Johnson T, Loeffler DR (2011) Cancer-related chronic pain: examining quality of life in diverse cancer survivors. Cancer. PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Kim ES (2015) Neuropathic caner pain: is it linked to the recurrence of cancer? Korean J Pain. 28(2):73–74. CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global Cancer Statistics: 2011. CA Cancer J Clin. Google Scholar
  4. 4.
    Chua KSG, Reddy SK, Lee MC, Patt RB (1999) Pain and loss of function in head and neck cancer survivors. J Pain Symptom Manage. PubMedCrossRefPubMedCentralGoogle Scholar
  5. 5.
    Roxburgh CSD, McMillan DC (2014) Cancer and systemic inflammation: treat the tumour and treat the host. Br J Cancer. 110(6):1409–1412. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Illi J, Miaskowski C, Cooper B et al (2012) Association between pro- and anti-inflammatory cytokine genes and a symptom cluster of pain, fatigue, sleep disturbance, and depression. Cytokine. PubMedPubMedCentralCrossRefGoogle Scholar
  7. 7.
    Laird BJA, Fallon M, Hjermstad MJ et al (2016) Quality of life in patients with advanced cancer: differential association with performance status and systemic inflammatory response. J Clin Oncol. PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Dantzer R (2004) Cytokine-induced sickness behaviour: a neuroimmune response to activation of innate immunity. Eur J Pharmacol. PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Cleeland CS, Bennett GJ, Dantzer R et al (2003) Are the symptoms of cancer and cancer treatment due to a shared biologic mechanism? A cytokine-immunologic model of cancer symptoms. Cancer. PubMedCrossRefPubMedCentralGoogle Scholar
  10. 10.
    Capuron L, Dantzer R (2003) Cytokines and depression: the need for a new paradigm. In: Brain, Behavior, and Immunity. In. CrossRefGoogle Scholar
  11. 11.
    Mirabile A, Airoldi M, Ripamonti C et al (2016) Pain management in head and neck cancer patients undergoing chemo-radiotherapy: clinical practical recommendations. Crit Rev Oncol Hematol. PubMedCrossRefPubMedCentralGoogle Scholar
  12. 12.
    Scharpf J, Karnell LH, Christensen AJ, Funk GF (2009) The role of pain in head and neck cancer recurrence and survivorship. Arch Otolaryngol - Head Neck Surg. CrossRefGoogle Scholar
  13. 13.
    Rogers LQ, Courneya KS, Robbins KT et al (2008) Factors associated with fatigue, sleep, and cognitive function among patients with head and neck cancer. Head Neck. CrossRefGoogle Scholar
  14. 14.
    Mehanna HM, Morton RP (2006) Does quality of life predict long-term survival in patients with head and neck cancer? Arch Otolaryngol - Head Neck Surg. CrossRefGoogle Scholar
  15. 15.
    Shinn EH, Valentine A, Jethanandani A et al (2016) Depression and oropharynx cancer outcome. Psychosom Med. PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Pinquart M, Duberstein PR (2010) Depression and cancer mortality: a meta-analysis. Psychol Med. PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Howren MB, Christensen AJ, Karnell LH ynd., Funk GF. Psychological factors associated with head and neck cancer treatment and survivorship: evidence and opportunities for behavioral medicine. J Consult Clin Psychol. 2013. doi: PubMedCrossRefPubMedCentralGoogle Scholar
  18. 18.
    Pendergrass JC, Targum SD, Harrison JE (2018) Cognitive impairment associated with cancer: a brief review. Innov Clin Neurosci.Google Scholar
  19. 19.
    Hart RP, Wade JB, Martelli MF (2003) Cognitive impairment in patients with chronic pain: the significance of stress. Curr Pain Headache Rep. PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Dufton BD (2005) Cognitive failure and chronic pain. Int J Psychiatry Med. 19(3):291–297. CrossRefGoogle Scholar
  21. 21.
    Rainville P, Duncan GH, Price DD, Carrier B, Bushnell MC (1997) Pain affect encoded in human anterior cingulate but not somatosensory cortex. Science (80- ). PubMedCrossRefGoogle Scholar
  22. 22.
    Chapman CR, Gavrin J (1999) Suffering: the contributions of persistent pain. Lancet. CrossRefGoogle Scholar
  23. 23.
    Sheline YI, Sanghavi M, Mintun MA, Gado MH (1999) Depression duration but not age predicts hippocampal volume loss in medically healthy women with recurrent major depression. J Neurosci. PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Apkarian AV (2004) Chronic back pain is associated with decreased prefrontal and thalamic gray matter density. J Neurosci. PubMedCrossRefGoogle Scholar
  25. 25.
    Ruether W, Ihle K, May A, Rodriguez-Raecke R, Niemeier A (2009) Brain gray matter decrease in chronic pain is the consequence and not the cause of pain. J Neurosci. PubMedCrossRefGoogle Scholar
  26. 26.
    May A (2008) Chronic pain may change the structure of the brain. Pain. PubMedCrossRefGoogle Scholar
  27. 27.
    Woolf CJ, Salter MW (2000) Neuronal plasticity: increasing the gain in pain. Science (80- ). PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Du MY, Wu QZ, Yue Q et al (2012) Voxelwise meta-analysis of gray matter reduction in major depressive disorder. Prog Neuro-Psychopharmacology Biol Psychiatry. PubMedCrossRefGoogle Scholar
  29. 29.
    Gustin SM, Peck CC, Macey PM, Murray GM, Henderson LA (2013) Unraveling the effects of plasticity and pain on personality. J Pain. PubMedCrossRefPubMedCentralGoogle Scholar
  30. 30.
    Johansen-Berg H, Gutman DA, Behrens TEJ et al (2008) Anatomical connectivity of the subgenual cingulate region targeted with deep brain stimulation for treatment-resistant depression. Cereb Cortex. PubMedCrossRefPubMedCentralGoogle Scholar
  31. 31.
    Younger JW, Chu LF, DArcy NT, Trott KE, Jastrzab LE, MacKey SC (2011) Prescription opioid analgesics rapidly change the human brain. Pain. PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Weber RJ, Gomez-Flores R, Smith JE, Martin TJ (2009) Neuronal adaptations, neuroendocrine and immune correlates of heroin self-administration. Brain Behav Immun. PubMedCrossRefPubMedCentralGoogle Scholar
  33. 33.
    Li Y, van den Pol AN (2008) Opioid receptor-mediated depression of the hypothalamic hypocretin/orexin arousal system. J Neurosci. 28(11):2814–2819. CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Rosow CE (1987) The clinical usefulness of agonist-antagonist analgesics in acute pain. Drug Alcohol Depend. PubMedCrossRefPubMedCentralGoogle Scholar
  35. 35.
    Xiao C, Hanlon A, Zhang Q et al (2013) Symptom clusters in patients with head and neck cancer receiving concurrent chemoradiotherapy. Oral Oncol. PubMedCrossRefGoogle Scholar
  36. 36.
    Denham JW, Hauer-Jensen M (2002) The radiotherapeutic injury - a complex “wound.”. Radiother Oncol. PubMedCrossRefGoogle Scholar
  37. 37.
    Krysko DV, Agostinis P, Krysko O et al (2011) Emerging role of damage-associated molecular patterns derived from mitochondria in inflammation. Trends Immunol. PubMedCrossRefGoogle Scholar
  38. 38.
    Srikrishna G, Freeze HH (2015) Endogenous damage-associated molecular pattern molecules at the crossroads of inflammation and cancer. Neoplasia. PubMedPubMedCentralCrossRefGoogle Scholar
  39. 39.
    Criswell T, Leskov K, Miyamoto S, Luo G, Boothman DA (2003) Transcription factors activated in mammalian cells after clinically relevant doses of ionizing radiation. Oncogene. PubMedCrossRefGoogle Scholar
  40. 40.
    Logan RM, Gibson RJ, Sonis ST, Keefe DMK (2007) Nuclear factor-κB (NF-κB) and cyclooxygenase-2 (COX-2) expression in the oral mucosa following cancer chemotherapy. Oral Oncol. PubMedCrossRefPubMedCentralGoogle Scholar
  41. 41.
    Al-Dasooqi N, Gibson RJ, Bowen JM, Keefe DM (2009) Matrix metalloproteinases: key regulators in the pathogenesis of chemotherapy-induced mucositis? Cancer Chemother Pharmacol. 64:1–9. CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Yang CA, Chiang BL (2015) Inflammasomes and human autoimmunity: a comprehensive review. J Autoimmun. PubMedCrossRefPubMedCentralGoogle Scholar
  43. 43.
    Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell. PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Cavaillon JM, Munoz C, Fitting C, Misset B, Carlet J (1992) Circulating cytokines: the tip of the iceberg? Circ ShockGoogle Scholar
  45. 45.
    Barcellos-Hoff MH (2006) How do tissues respond to damage at the cellular level? The role of cytokines in irradiated tissues. Radiat Res. PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Mejias NH, Martinez CC, Stephens ME, De Rivero Vaccari JP (2018) Contribution of the inflammasome to inflammaging. J Inflamm (United Kingdom).
  47. 47.
    MOLE RH (1953) Whole body irradiation; radiobiology or medicine? Br J Radiol. PubMedCrossRefPubMedCentralGoogle Scholar
  48. 48.
    Ciofi P, Garret M, Lapirot O et al (2009) Brain-endocrine interactions: a microvascular route in the mediobasal hypothalamus. Endocrinology. PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Schubert C, Hong S, Natarajan L, Mills PJ, Dimsdale JE (2007) The association between fatigue and inflammatory marker levels in cancer patients: a quantitative review. Brain Behav Immun. 21(4):413–427. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Allen A, Flynn J, Mahadevan A et al (2009) Randomized phase 2 study of concomitant chemoradiotherapy using weekly carboplatin/paclitaxel with or without daily subcutaneous amifostine in patients with locally advanced head and neck cancer. Cancer. 115(19):4514–4523. CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Russi EG, Raber-Durlacher JE, Sonis ST (2014) Local and systemic pathogenesis and consequences of regimen-induced inflammatory responses in patients with head and neck cancer receiving chemoradiation. Mediators Inflamm. 2014:1–14. CrossRefGoogle Scholar
  52. 52.
    Clarkson JE, Worthington HV, Furness S, McCabe M, MS KT, Hv W, Furness S, Mccabe M, Khalid T, Meyer S (2010) Interventions for treating oral mucositis for patients with cancer receiving treatment ( Review ). Cochrane Libr. (8).
  53. 53.
    Epstein JB, Truelove EL, Oien H, Allison C, Le ND, Epstein MS (2001) Oral topical doxepin rinse: analgesic effect in patients with oral mucosal pain due to cancer or cancer therapy. Oral Oncol. PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Lalla RV, Bowen J, Barasch A et al (2014) MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer. PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Allison RR, Ambrad AA, Arshoun Y et al (2014) Multi-institutional, randomized, double-blind, placebo-controlled trial to assess the efficacy of a mucoadhesive hydrogel (MuGard) in mitigating oral mucositis symptoms in patients being treated with chemoradiation therapy for cancers of the head and neck. Cancer. PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Sarvizadeh M, Meidani M, Roayaei M, Hemati S, Shahsanai A, Ashouri M (2015) Morphine mouthwash for the management of oral mucositis in patients with head and neck cancer. Adv Biomed Res. 4(1):44. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Bandieri E, Romero M, Ripamonti CI et al (2016) Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain. J Clin Oncol. PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Takase H, Sakata T, Yamano T, Sueta T, Nomoto S, Nakagawa T (2011) Advantage of early induction of opioid to control pain induced by irradiation in head and neck cancer patients. Auris Nasus Larynx. PubMedCrossRefGoogle Scholar
  59. 59.
    Kestenbaum MG, Vilches AO, Messersmith S et al (2014) Alternative routes to oral opioid administration in palliative care: a review and clinical summary. Pain Med (United States). PubMedCrossRefPubMedCentralGoogle Scholar
  60. 60.
    Bell BC, Butler EB (2013) Management of predictable pain using fentanyl pectin nasal spray in patients undergoing radiotherapy. J Pain Res.
  61. 61.
    Mazzotta M, Bossi P, Filetti M, Iacono D, Marchetti P, Giusti R (2017) The use of fentanyl in pain management in head and neck cancer patients: a narrative review. Br J Pain. 12(3):155–162. CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Hess R, Stiebler G, Herz A (1972) Pharmacokinetics of fentanyl in man and the rabbit. Eur J Clin Pharmacol. PubMedCrossRefGoogle Scholar
  63. 63.
    Grond S, Zech D, Lehmann KA, Radbruch L, Breitenbach H, Hertel D (1997) Transdermal fentanyl in the long-term treatment of cancer pain: a prospective study of 50 patients with advanced cancer of the gastrointestinal tract or the head and neck region. Pain. PubMedCrossRefGoogle Scholar
  64. 64.
    Bossi P, Locati L, Bergamini C et al (2014) Fentanyl pectin nasal spray as treatment for incident predictable breakthrough pain (BTP) in oral mucositis induced by chemoradiotherapy in head and neck cancer. Oral Oncol. PubMedCrossRefGoogle Scholar
  65. 65.
    Schug SA, Ting S (2017) Fentanyl formulations in the management of pain: an update. Drugs. 77:747–763. CrossRefPubMedGoogle Scholar
  66. 66.
    Chang A, Roeland EJ, Atayee RS, Revta C, Ma JD (2015) Transmucosal immediate-release fentanyl for breakthrough cancer pain: opportunities and challenges for use in palliative care. J Pain Palliat Care Pharmacother. CrossRefGoogle Scholar
  67. 67.
    Zeppetella G, Davies AN (2015) Opioids for the management of breakthrough pain in cancer patients. Cochrane Database Syst Rev.
  68. 68.
    Paice JA, Von Roenn JH (2014) Under- or overtreatment of pain in the patient with cancer: how to achieve proper balance. J Clin Oncol. PubMedCrossRefGoogle Scholar
  69. 69.
    Hanna B, Cohen E, Leach S, Boyd S, Botti M, Robbins J (2009) Pain beliefs and pain management of oncology patients. Cancer Nurs. 31(2):E1–E8. CrossRefGoogle Scholar
  70. 70.
    Enting RH, Oldenmenger WH, Van Gool AR, van der Rijt CCD, Sillevis Smitt PAE (2007) The effects of analgesic prescription and patient adherence on pain in a dutch outpatient cancer population. J Pain Symptom Manage. PubMedCrossRefPubMedCentralGoogle Scholar
  71. 71.
    Lalla RV, Choquette LE, Curley KF et al (2014) Randomized double-blind placebo-controlled trial of celecoxib for oral mucositis in patients receiving radiation therapy for head and neck cancer. Oral Oncol. PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Yennurajalingam S, Frisbee-Hume S, Palmer JL et al (2013) Reduction of cancer-related fatigue with dexamethasone: a double-blind, randomized, placebo-controlled trial in patients with advanced cancer. J Clin Oncol. PubMedCrossRefPubMedCentralGoogle Scholar
  73. 73.
    Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ, Moore M (2009) Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev.
  74. 74.
    Jiang J, Li Y, Shen Q et al (2019) Effect of pregabalin on radiotherapy-related neuropathic pain in patients with head and neck cancer: a randomized controlled trial. J Clin Oncol. PubMedCrossRefPubMedCentralGoogle Scholar
  75. 75.
    Jain MK, Ridker PM (2005) Anti-inflammatory effects of statins: Clinical evidence and basic mechanisms. Nat Rev Drug Discov. PubMedCrossRefPubMedCentralGoogle Scholar
  76. 76.
    Kvillemo P, Bränström R (2011) Experiences of a mindfulness-based stress-reduction intervention among patients with cancer. Cancer Nurs. PubMedCrossRefPubMedCentralGoogle Scholar
  77. 77.
    Mustian KM (2013) Yoga as treatment for insomnia among cancer patients and survivors: a systematic review. Eur Med journal Oncol.Google Scholar
  78. 78.
    Adair M, Murphy B, Yarlagadda S, Deng J, Dietrich MS, Ridner SH (2018) Feasibility and preliminary efficacy of tailored yoga in survivors of head and neck cancer: a pilot study. Integr Cancer Ther. PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    Rogers LQ, Malone J, Rao K et al (2009) Exercise preferences among patients with head and neck cancer: prevalence and associations with quality of life, symptom severity, depression, and rural residence. Head Neck. CrossRefGoogle Scholar
  80. 80.
    van Nieuwenhuizen AJ, Buffart LM, van Uden-Kraan CF et al (2018) Patient-reported physical activity and the association with health-related quality of life in head and neck cancer survivors. Support Care Cancer. 26:1087–1095. CrossRefPubMedPubMedCentralGoogle Scholar
  81. 81.
    Lopez G, Garcia MK, Liu W et al (2018) Outpatient acupuncture effects on patient self-reported symptoms in oncology care: a retrospective analysis. J Cancer. PubMedPubMedCentralCrossRefGoogle Scholar

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© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Medical OncologyASST Spedali Civili BresciaBresciaItaly
  2. 2.Department of Medical and Surgical Specialties, Radiological Sciences and Public HealthUniversity of BresciaBresciaItaly
  3. 3.Oncology DepartmentA. Businco HospitalCagliariItaly
  4. 4.Radiation Oncology DepartmentIstituto Nazionale Tumori-IRCCS-G. Pascale FoundationNaplesItaly
  5. 5.Oncology and Haematology DepartmentUniversity Hospital of Modena and Reggio EmiliaModenaItaly

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