Drug-associated non-pyrogenic hyperthermia: a narrative review



Hyperthermia occurs when heat accumulation surpasses the body’s ability for heat dissipation. Many drugs may affect thermoregulation. This narrative review aimed to provide an overview of the current literature concerning reports of drug-associated non-pyrogenic hyperthermia.


A comprehensive search was performed across 5 databases covering the period of inception to March 2019, for publications that reported hyperthermia associated with drug use. Studies that reported potential drug association with hyperthermia due to altered thermoregulatory mechanisms were included. Case reports of less than 3 cases were excluded, as well as hyperthermia due to other causes, such as hypersensitivity, malignant hyperthermia and neuroleptic malignant syndrome. The primary outcomes of interest were hospitalisation and mortality.


The literature search initially identified a total of 2609 records. Based on full-text analysis, 11 articles met the inclusion criteria, of which there were 5 case-control studies, 2 case series and 4 retrospective analyses. Studies reported heat-related hospitalisations or emergency department presentations associated with the use of psychotropics (antipsychotics, antidepressants and anxiolytics), anticholinergics, antihistamines, diuretics, cardiovascular agents, non-steroidal anti-inflammatory drugs and anticoagulants. Psychotropic drugs were reported to be associated with increased heat-related mortality, other than through neuroleptic malignant syndrome, but findings varied among the studies.


Given the relative lack of publications, more research is necessary to study specific effects of drugs on body temperature and the likelihood of inducing non-pyrogenic hyperthermia. In particular, psychotropics, anticholinergics, diuretics and cardiovascular agents are of interest for future studies.

This is a preview of subscription content, log in to check access.

Access options

Buy single article

Instant unlimited access to the full article PDF.

US$ 39.95

Price includes VAT for USA

Subscribe to journal

Immediate online access to all issues from 2019. Subscription will auto renew annually.

US$ 199

This is the net price. Taxes to be calculated in checkout.

Fig. 1
Fig. 2


  1. 1.

    Atha WF (2013) Heat-related illness. Emerg Med Clin North Am 31(4):1097–1108

  2. 2.

    Musselman ME, Saely S (2013) Diagnosis and treatment of drug-induced hyperthermia. Am J Health Syst Pharm 70(1):34–42

  3. 3.

    Kurz A (2008) Physiology of thermoregulation. Best Pract Res Clin Anaesthesiol 22(4):627–644

  4. 4.

    Halloran LL, Bernard DW (2004) Management of drug-induced hyperthermia. Curr Opin Pediatr 16(2):211–215

  5. 5.

    Morrison SF, Nakamura K (2019) Central mechanisms for thermoregulation. Annu Rev Physiol 81:285–308

  6. 6.

    Buggy DJ, Crossley AW (2000) Thermoregulation, mild perioperative hypothermia and postanaesthetic shivering. Br J Anaesth 84(5):615–628

  7. 7.

    Dao CK, Nowinski SM, Mills EM (2014) The heat is on: molecular mechanisms of drug-induced hyperthermia. Temperature (Austin) 1(3):183–191

  8. 8.

    Waters TA (2001) Heat illness: tips for recognition and treatment. Cleve Clin J Med 68(8):685–687

  9. 9.

    Hifumi T, Kondo Y, Shimizu K, Miyake Y (2018) Heat stroke. J Intensive Care 6:30

  10. 10.

    Kenny GP, Yardley J, Brown C, Sigal RJ, Jay O (2010) Heat stress in older individuals and patients with common chronic diseases. CMAJ 182(10):1053–1060

  11. 11.

    Becker JA, Stewart LK (2011) Heat-related illness. Am Fam Physician 83(11):1325–1330

  12. 12.

    Levine M, LoVecchio F, Ruha AM, Chu G, Roque P (2012) Influence of drug use on morbidity and mortality in heatstroke. J Med Toxicol 8(3):252–257

  13. 13.

    Hajat S, O'Connor M, Kosatsky T (2010) Health effects of hot weather: from awareness of risk factors to effective health protection. Lancet 375(9717):856–863

  14. 14.

    Westaway K, Frank O, Husband A, McClure A, Shute R, Edwards S, Curtis J, Rowett D (2015) Medicines can affect thermoregulation and accentuate the risk of dehydration and heat-related illness during hot weather. J Clin Pharm Ther 40(4):363–367

  15. 15.

    Johnson DH, Cunha BA (1996) Drug fever. Infect Dis Clin N Am 10(1):85–91

  16. 16.

    Argaud L, Ferry T, Le QH, Marfisi A, Ciorba D, Achache P, Ducluzeau R, Robert D (2007) Short- and long-term outcomes of heatstroke following the 2003 heat wave in Lyon, France. Arch Intern Med 167(20):2177–2183

  17. 17.

    Walter E, Carraretto M (2015) Drug-induced hyperthermia in critical care. J Intensive Care Soc 16(4):306–311

  18. 18.

    Kalisch Ellett LM, Pratt NL, Le Blanc VT, Westaway K, Roughead EE (2016) Increased risk of hospital admission for dehydration or heat-related illness after initiation of medicines: a sequence symmetry analysis. J Clin Pharm Ther 41(5):503–507

  19. 19.

    Martin-Latry K, Goumy M-P, Latry P, Gabinski C, Begaud B, Faure I, Verdoux H (2007) Psychotropic drugs use and risk of heat-related hospitalisation. Eur Psychiatry 22(6):335–338

  20. 20.

    Pui-yin Chung J, Shiu-yin Chong C, Chung KF, Lai-wah Dunn E, Wai-nang Tang O, Chan WF (2008) The incidence and characteristics of clozapine- induced fever in a local psychiatric unit in Hong Kong. Can J Psychiatr Rev Can Psychiatr 53(12):857–862

  21. 21.

    Davido A, Patzak A, Dart T, Sadier MP, Meraud P, Masmoudi R, Sembach N, Cao TH (2006) Risk factors for heat related death during the August 2003 heat wave in Paris, France, in patients evaluated at the emergency department of the Hopital Europeen Georges Pompidou. Emerg Med J 23(7):515–518

  22. 22.

    Misset B, De Jonghe B, Bastuji-Garin S, Gattolliat O, Boughrara E, Annane D, Hausfater P, Garrouste-Orgeas M, Carlet J (2006) Mortality of patients with heatstroke admitted to intensive care units during the 2003 heat wave in France: a national multiple-center risk-factor study. Crit Care Med 34(4):1087–1092

  23. 23.

    Vodovar D, LeBeller C, Megarbane B, Lillo-Le-Louet A, Hanslik T (2012) Drug fever: a descriptive cohort study from the French national pharmacovigilance database. Drug Saf 35(9):759–767

  24. 24.

    Sommet A, Durrieu G, Lapeyre-Mestre M, Montastruc JL (2012) A comparative study of adverse drug reactions during two heat waves that occurred in France in 2003 and 2006. Pharmacoepidemiol Drug Saf 21(3):285–288

  25. 25.

    Michenot F, Sommet A, Bagheri H, Lapeyre-Mestre M, Montastruc JL (2006) Adverse drug reactions in patients older than 70 years during the heat wave occurred in France in summer 2003: a study from the French PharmacoVigilance Database. Pharmacoepidemiol Drug Saf 15(10):735–740

  26. 26.

    Martinez M, Devenport L, Saussy J, Martinez J (2002) Drug-associated heat stroke. South Med J 95(8):799–802

  27. 27.

    Hochegger K, Rudnicki M, Auinger M, Mark W, Margreiter R, Mayer G, Rosenkranz AR (2009) Fever of unknown origin in renal transplant patients with tacrolimus. Clin Transpl 23(4):575–579

  28. 28.

    Stollberger C, Lutz W, Finsterer J (2009) Heat-related side-effects of neurological and non-neurological medication may increase heatwave fatalities. Eur J Neurol 16(7):879–882

  29. 29.

    Abdelmoety DA, El-Bakri NK, Almowalld WO, Turkistani ZA, Bugis BH, Baseif EA, Melbari MH, AlHarbi K, Abu-Shaheen A (2018) Characteristics of heat illness during hajj: a cross-sectional study. Biomed Res Int 2018:1–6

  30. 30.

    Walter AN, Lenz TL (2011) Hydration and medication use. Am J Lifestyle Med 5(4):332–335

  31. 31.

    Hazell L, Shakir SA (2006) Under-reporting of adverse drug reactions: a systematic review. Drug Saf 29(5):385–396

Download references

Author information

KSB, MSS and GMP designed the project, reviewed publications and wrote the manuscript. KSB performed the literature searches.

Correspondence to Gregory M. Peterson.

Ethics declarations

Conflict of interest

The authors declare that they have no conflicts of interest.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key points

• With the expected increasing global temperatures in the coming decades, heat-related mortality will rise. Identification of possible factors which can contribute to hyperthermia, including specific drug use, is of utmost importance.

• This review found that drugs reportedly associated with non-pyrogenic hyperthermia varied, with the primary groups being psychotropics, anticholinergics, diuretics and cardiovascular drugs.

• More research is necessary to identify the mechanisms, risk factors and incidence of drug-associated hyperthermia.

Electronic supplementary material


(DOCX 15 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Bongers, K.S., Salahudeen, M.S. & Peterson, G.M. Drug-associated non-pyrogenic hyperthermia: a narrative review. Eur J Clin Pharmacol 76, 9–16 (2020) doi:10.1007/s00228-019-02763-5

Download citation


  • Hyperthermia
  • Non-pyrogenic
  • Heat stroke
  • Heat exhaustion
  • Thermoregulation
  • Drug-associated
  • Adverse drug reactions
  • Hospitalisation