Abstract
Opioid-induced respiratory depression is potentially life-threatening and often regarded as the main hazard of opioid use. Main cause of death is cardiorespiratory arrest with hypoxia and hypercapnia. Respiratory depression is mediated by opioid μ receptors expressed on respiratory neurons in the CNS. Studies on the major sites in the brainstem mediating respiratory rate suppression, the pre-Bӧtzinger complex and parabrachial complex (including the Kӧlliker Fuse nucleus), have yielded conflicting findings and interpretations but recent investigations involving deletion of μ receptors from neurons have led to greater consensus. Some opioid analgesic drugs are histamine releasers. The range of clinical effects of released histamine include increased cardiac output due to an increase in heart rate, increased force of myocardial contraction, and a dilatatory effect on small blood vessels leading to flushing, decreased vascular resistance and hypotension. Resultant hemodynamic changes do not necessarily relate directly to the concentration of histamine in plasma due to a range of variables including functional differences between mast cells and histamine-induced anaphylactoid reactions may occur less often than commonly believed. Opioid-induced histamine release rarely if ever provokes bronchospasm and histamine released by opioids in normal doses does not lead to anaphylactoid reactions or result in IgE-mediated reactions in normal patients. Hypersensitivities to opioids, mainly some skin reactions and occasional type I hypersensitivities, chiefly anaphylaxis and urticaria, are uncommon. Hypersensitivities to morphine, codeine, heroin, methadone, meperidine, fentanyl, remifentanil, buprenorphine, tramadol, and dextromethorphan are summarized. In 2016, the FDA issued a Drug Safety Communication concerning the association of opioids with serotonin syndrome, a toxicity associated with raised intra-synaptic concentrations of serotonin in the CNS, inhibition of serotonin reuptake, and activation of 5-HT receptors. Opioids may provoke serotonin toxicity especially if administered in conjunction with other serotonergic medications. The increasing use of opioid analgesics and widespread prescribing of antidepressants and psychiatric medicines, indicates the likelihood of an increased incidence of serotonin toxicity in opioid-treated patients.
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References
Aguilera-Castro F (2017) Intraoperative recurrence of probable allergic reaction to remifentanil. Case Report Rev Colomb Anestesiol 45(Suppl 1):131–135. https://doi.org/10.1016/j.rcae.2016.05.001
Anibarro B, Vila C, Seoane FJ (2000) Urticaria induced by pethidine allergy. Allergy 55:305–306
Anonymous (1998) Tramadol and anaphylactic reactions. Bull SADRAC 67:3–4
Asero R (2003) Chronic urticaria with multiple NSAID intolerance: is tramadol always a safe alternative analgesic? J Investig Allergol Clin Immunol 13:56–59
Australian Public Assessment Report for Tapentadol, 2011. Therapeutic goods administration (TGA), Australia. https://www.tga.gov.au/sites/default/files/auspar-palexia.pdf. Accessed 20 Mar 2021
Bachmutsky I, Wei XP, Kish E et al (2020) Opioids depress breathing through two small brainstem sites. eLife 9:e52694. https://doi.org/10.7554/eLife.52694
Baldo BA (2017) Editorial. Opioid analgesic drugs: misuse, toxicity, and hypersensitivity. J Allergy Clin Immunol 5:1607–1608
Baldo BA (2018) Opioid analgesic drugs and serotonin toxicity (syndrome): mechanisms, animal models, and links to clinical effects. Arch Toxicol 92:2457–2473
Baldo BA, Pham NH (2021) Drug allergy: clinical aspects, diagnosis, mechanisms structure-activity relationships. Springer, New York, pp 418–424
Baldo BA, Rose M (2020) The anaesthetist, opioid analgesic drugs and serotonin toxicity: a mechanistic and clinical perspective. Brit J Anaesth 124:44–62
Baldo BA, Pham NH, Zhao Z (2001) Chemistry of drug allergenicity. Curr Opin Allergy Clin Immunol 1:327–335
Barann M, Stamer UM, Lyutenska M et al (2015) Effects of opioids on human serotonin transporters. Naunyn Schmiedeberg’s Arch Pharmacol 388:43–49
Barke KE, Hough LB (1993) Opiates, mast cells and histamine release. Life Sci 53:1391–1399
Barth H, Giertz H, Schmal A et al (1987) Anaphylactoid reactions and histamine release do not occur after application of the opioid tramadol. Agents Act 20:310–313
Bennett MJ, Anderson LK, McMillan JC (1986) Anaphylactic reaction during anaesthesia associated with positive intradermal skin test to fentanyl. Can Anaesth Soc J 33:75–78
Blunk JA, Schmelz M, Zeck S et al (2004) Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin. Anesth Analg 98:364–370
Boggs CL, Ripple MG, Ali Z et al (2013) Anaphylaxis after the injection of buprenorphine. J Forensic Sci 58:1381–1383
Boileau S, Hummer-Sigiel M, Moeller R et al (1985) Reevaluation des risques respectifs d’anaphylaxie et d’histaminoliberation avec les substances anesthesiologiques. Ann Fr Anesth Reanim 4:195–204
Bollig G, Gremmelt A (2014) Possible anaphylactic reaction to transdermal buprenorphine. Research 1:860–861
Bowdle TA, Even A, Shen DD (2004) Methadone for the induction of anesthesia: plasma histamine concentration, arterial blood pressure, and heart rate. Anesth Analg 98:1692–1697
Boyer EW, Shannon M (2005) The serotonin syndrome. N Eng J Med 352:1112–1120
Bruera E, Fainsinger R, Moore R et al (1991) Local toxicity with subcutaneous methadone. Pain 45:141–143
Buckley NA, Dawson AH, Isbister GK (2014) Serotonin syndrome. Brit Med J 348:g1626. https://doi.org/10.1136/bmj.g1626
Butler EB (1951) A case of hypersensitivity to pethidine in a woman in labour. Br Med J 2:715–716
Casale TB, Bowman S, Kaliner M (1984) Induction of human cutaneous mast cell degranulation by opiates and endogenous opioid peptides: evidence for opiate and nonopiate receptor participation. J Allergy Clin Immunol 73:775–781
Cashman JN, Dolin SJ (2004) Respiratory and haemodynamic effects of acute postoperative pain management: evidence from published data. Br J Anaesth 93:212–6223
Catley DM, Thornton C, Jordan C et al (1985) Pronounced episodic oxygen desaturation in the postoperative period: its association with ventilatory pattern and analgesic regime. Anesthesiology 63:20–28
Codd EE, Shank RP, Schupsky JJ et al (1995) Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics. J Pharmacol Exp Ther 274:1263–1270
Conde-Salazar L, Guimaraens D, Gonzalez M et al (1991) Occupational allergic contact dermatitis from opium alkaloids. Contact Dermatitis 25:202–203
Corson EF, Rouse GP Jr (1946) Contact dermatitis from morphine; a series of cases among workers in a drug factory. Pa Med J 49:968–970
Crabbe Erush S (1996) Narcotic Allergy. Pharm Ther 21:250–252
Cromwell TA, Tzigmond EK (1974) Hypersensitivity to intravenous morphine sulfate. Plast Reconstr Surg 54:224–227
Cummings KC, Arnaut K (2007) Case report: fentanyl-associated intraoperative anaphylaxis with pulmonary edema. Can J Anesth 54:301–306
Dahan A, Sarton E, Teppema L et al (2001) Anesthetic potency and influence of morphine and sevoflurane on respiration in μ-opioid receptor knockout mice. Anesthesiology 94:824–832
Dahan A, Aarts L, Smith TW (2010) Incidence, reversal, and prevention of opioid-induced respiratory depression. Anesthesiology 112:226–238
Dahan A, Overdyk F, Smith T (2013) Pharmacovigilance: a review of opioid-induced respiratory Subsequent depression in chronic pain patients. Pain Physician 16:E85–E94
De Cuyper C, Goeteyn M (1992) Systemic contact dermatitis from subcutaneous hydromorphone. Contact Dermat 27:220–223
Dewachter P, Lefebvre D, Kalaboka S et al (2009) An anaphylactic reaction to transdermal delivered fentanyl. Acta Anaesthesiol Scand 53:1092–1093
Dhingra RR, Dutschmann M, Galán RF et al (2017) Kölliker-Fuse nuclei regulate respiratory rhythm variability via a gain-control mechanism. Am J Physiol Regul Integr Comp Physiol 312:R172–R188
Dong SW, Mertes PM, Petitpain N (2012) Hypersensitivity reactions during anesthesia. Results from the ninth French survey (2005–2007). Minerva Anestesiol 78:868–878
Driessen B, Reimann W (1992) Interaction of the central analgesic, tramadol, with the uptake and release of 5-hydroxytryptamine in the rat brain in vitro. Br J Pharmacol 105:147–151
Dunkley EJ, Isbister GK, Sibbritt D et al (2003) The hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity. QJM 96:635–642
Dutschmann M, Dick TE (2012) Pontine mechanisms of respiratory control. Compr Physiol 2:2443–2469
Dutschmann M, Herbert H (2006) The Kölliker-Fuse nucleus gates the postinspiratory phase of the respiratory cycle to control inspiratory off-switch and upper airway resistance in rat. Eur J Neurosci 24:1071–1084. https://doi.org/10.1111/j.1460-9568.2006.04981.xAccessed22March,2021
Eckenoff JE, Oech SR (1960) The effects of narcotics and antagonists upon respiration and circulation in man. Clin Pharmacol Ther 1:483–524
Edston E, van Hage-Hamsten M (1997) Anapylactoid shock—a common cause of death in heroin addicts? Allergy 52:950–954
Estrada JL, Puebla MJ, de Urbina JJ et al (2001) Generalized eczema due to codeine. Contact Dermatitis 44:185
Ezure K, Tanaka I (2006) Distribution and medullary projection of respiratory neurons in the dorsolateral pons of the rat. Neuroscience 141:1011–1023
Fahmy NR (1981) Hemodynamics, plasma histamine, and catecholamine concentrations during an anaphylactoid reaction to morphine. Anesthesiology 55:329–331
FDA Drug safety communications (2016) FDA warns about several safety issues with opioid pain medicines; requires label changes. March 22, 2016. https://www.fda.gov/downloads/Drugs/DrugSafety/UCM491302.pdf. Accessed 20 Mar 2021
Feldberg W, Paton WDM (1950) The release of histamine by morphine alkaloids. J Physiol 111:19P
Feldberg W, Paton WDM (1951) Release of histamine from skin and muscle in the cat by opium alkaloids and other histamine liberators. J Physiol 114:490–509
Fineschi V, Cecchi R, Centini F et al (2001) Immunohistochemical quantification of pulmonary mast-cells and post-mortem blood dosages of tryptase and eosinophil cationic protein in 48 heroin-related deaths. Forensic Sci Int 120:189–194
Fisher MM (1988) Direct histamine release in anaesthesia and surgery: unanswered questions. Theoretical Surg 3:145–147
Fisher MM, Baldo BA (2000) Immunoassays in the diagnosis of anaphylaxis to neuromuscular blocking drugs: the value of morphine for the detection of IgE antibodies in allergic subjects. Anaesth Intensive Care 28:167–170
Fisher MM, Harle DG, Baldo BA (1991) Anaphylactoid reactions to narcotic analgesics. Clin Rev Allergy 9:309–318
Fisher MM, Ramakrishnan N, Doig G et al (2009) The investigation of bronchospasm during induction of anaesthesia. Acta Anaesthesiol Scand 53:1006–1011
Fisher MM, Jones K, Rose M (2011) Follow-up after anaesthetc anaphylaxis. Acta Anaesthesiol Scand 55:99–103
Flacke JW, Flacke WE, Bloor BC (1987) Histamine release by four narcotics: a double-blind study in humans. Anesth Analg 66:723–730
Freye E (2008) Opioids in Medicine. Springer, Dordrecht, p 2008
Fukuda T, Dohi S (1986) Anaphylactic reaction to fentanyl or preservative. Can J Anaesth 33:826–827
Gayle JA, Volpi-Abadie J, Kaye AM (2015) Serotonin syndrome. In: Kaye AD, Kaye AM, Urman RD (eds) Essentials of pharmacology for anesthesia, pain medicine, and critical care. Springer, New York, pp 797–807
Geerling JC, Yokota S, Rukhadze I et al (2017) Kölliker-Fuse GABAergic and glutamatergic neurons project to distinct targets. J Comp Neurol 525:1844–1860
Ghislain PD, Wiart T, Bouhassoun N et al (1999) Toxicodermie au tramadol. Ann Dermatol Venereol 126:38–40
Gillman PK (2006a) A review of serotonin toxicity data: Implications for the mechanisms of antidepressant drug action. Biol Psychiatry 59:1046–1051
Gillman PK (2006b) Extracting value from case reports: lessons from serotonin toxicity. Anaesthesia 61:419–422
Gillman PK, Whyte IM (2004) Serotonin syndrome. In: Haddad P, Dursun S, Deakin B (eds) Adverse syndromes and psychiatric drugs. Oxford University Press, Oxford, pp 37–49
Giusti P, Buriani A, Cima L et al (1997) Effect of acute and chronic tramadol on [3H]-5-HT uptake in rat cortical synaptosomes. Br J Pharmacol 122:302–306
Gooch I, Gwinnutt C (2006) Anaphylaxis to intrathecal diamorphine. Resuscitation 70:470–473
Grassmann C (2008) An unusual adverse reaction to tramadol. Anaesthesia 63:442
Grond S, Sablotzki A (2004) Clinical pharmacology of tramadol. Clin Pharmacokinet 43:879–923
Grundy HF (1971) Cardiovascular effects of morphine, pethidine, diamorphine and nalorphine on the cat and rabbit. Br J Phamacol 42:159–178
Gupta K, Prasad A, Nagappa M et al (2018) Risk factors for opioid-induced respiratory depression and failure to rescue: a review. Curr Opin Anesthesiol 31:110–119
Harle DG, Baldo BA, Coroneos NJ et al (1989) Anaphylaxis following administration of papaveretum. Case Report: implication of IgE antibodies that react with morphine and codeine, and identification of an allergenic determinant. Anesthesiology 71:489–494
Harle DG, Baldo BA, Fisher MM (1990) Immunoassays employing substituted ammonium compounds other than neuromuscular blocking drugs to increase the detection of IgE antibodies to these drugs. Mol Immunol 27:1039–1045
Hermens JM, Ebertz JM, Hanifin JM et al (1985) Comparison of histamine release in human skin mast cells induced by morphine, fentanyl, and oxymorphone. Anesthesiology 62:124–129
Hirshman CA, Downes H, Butler J (1982) Relevance of plasma histamine levels to hypotension. Anesthesiology 57:424–425
Hogan-Esch AJ, van der Helde S, van den Brink W et al (2006) Contact allergy and respiratory/mucosal complaints from heroin (diacetylmorphine). Contact Dermat 54:42–49
Holmes J, Maye JP (2004) Postoperative respiratory depression and unresponsiveness following epidural opiate administration: a case report. AANA 72:126–128
Hunskaar S, Dragsund S (1985) Scarlatiniform rash and urticaria due to codeine. Ann Allergy 55:240–241
Hvid L, Svendsen MT, Andersen KE (2016) Occupational contact dermatitis caused by heroin (diacetylmorphine) and morphine. Contact Dermat 74:301–302
Isbister GK, Buckley NA (2005) The pathophysiology of serotonin toxicity in animals and humans. Implications for diagnosis and treatment. Clin Neuropharmacol 28:205–214
Isbister GK, Buckley NA, Whyte IM (2007) Serotonin toxicity: a practical approach to diagnosis and treatment. Med J Aust 187:361–365
Joo J, Bae H, Lee J (2009) Intraoperative allergic reaction to fentanyl—a case report. Korean J Anesthesiol 57:776–779
Kaae J, Menné T, Thyssen JP (2012) Systemic contact dermatitis following oral exposure to tramadol in a patient with allergic contact dermatitis caused by buprenorphine. Contact Dermat 66:106–107
Kaliner M, Shelhamer JH, Ottesen EA (1982) Effects of infused histamine: correlation of plasma histamine levels and symptoms. J Allergy Clin Immunol 69:283–289
Kartal M, Oktay C, Gözlükaya AB et al (2009) A rare diagnosis in emergency department: morphine related anaphylactoid reaction. Turk J Emerg Med 9:181–183
Kehm JC, Mack FE, Schlobohm RM (1970) The hemodynamic changes of large doses of morphine in humans. Abstr Am Soc Anesthesiol Annu Meet 1970:129
Kishimoto K, Koyama S, Akaike N (2001) Synergistic μ-opioid and 5-HT1A presynaptic inhibition of GABA release in rat periaqueductal gray neurons. Neuropharmacol 5:529–538
Knowles SR, Weber E (1998) Dextromethorphan anaphylaxis. J Allergy Clin Immunol 102:316–317
Kyrklund C, Hyry H, Alanko K (2013) Allergic contact dermatitis caused by transdermal buprenorphine. Contact Dermat 69:60–61
Lalley PM (2003) μ-Opioid receptor agonist effects on medullary respiratory neurons in the cat: evidence for involvement in certain types of ventilatory disturbances. Am J Physiol Regul Integr Comp Physiol 285:R1287–R1304
Lalley PM, Pilowsky PM, Forster HV et al (2014) CrossTalk opposing view: the pre-Bӧtzinger complex is not essential for respiratory depression following systemic administration of opioid analgesics. J Physiol 592:1163–1166
Laroche D, Chollet-Martin S, Léturgie P et al (2011) Evaluation of a new routine diagnostic test for immunoglobulin E sensitization to neuromuscular blocking agents. Anesthesiology 114:91–97
Lavezzi AM, Ottaviani G, Rossi L et al (2004) Cytoarchitectural organization of the parabrachial/Kölliker-Fuse complex in man. Brain Dev 26:316–320. https://doi.org/10.1016/j.braindev.2003.09.002 Accessed 22 Mar 2021
Lawrence ID, Warner JA, Cohan VL et al (1987) Purification and characterization of human skin mast cells. Evidence for human mast cell heterogeneity. J Immunol 139:3062–3069
Lee LA, Caplan RA, Stephens LS et al (2015) Postoperative opioid-induced respiratory depression: a closed claims analysis. Anesthesiology 122:659–665
Levitt ES, Abdala AP, Paton JFR et al (2015) μ Opioid receptor activation hyperpolarizes respiratory-controlling Kӧlliker–Fuse neurons and suppresses post-inspiratory drive. J Physiol 593:4453–4469
Levy JH (1986) Anaphylactic reactions in anesthesia and intensive care. Butterworths, Boston, p 1986
Levy JH, Rockoff MA (1982) Anaphylaxis to pethidine. Anesth Analg 61:301–303
Levy JH, Brister NW, Shearin A et al (1989) Wheal and flare responses to opioids in humans. Anesthesiology 70:756–760
Li PH, Ue KL, Wagner A et al (2017) Opioid hypersensitivity: Predictors of allergy and role of drug provocation testing. J Allergy Clin Immunol Pract 5:1601–1606
Liu S, Kim D, Oh TG et al (2020) Neural basis of opioid-induced respiratory depression and its rescue. BioRxiv. https://doi.org/10.1101/2020.10.28.359893
Lopez-Marina V, Pizarro-Romero G, Costa-Bardaja N (2006) Neumonitis por hipersensibilidad asociada a tramadol. Med Clin (barcelona) 126:77–78
Lorenz W (1975) Histamine release in man. Agents Act 5:402–416
Lorenz W, Doenicke A (1978) Histamine release in clinical conditions. Mt Sinai J Med 45:357–386
Lorenz W, Doenicke A, Schoning B et al (1982) Definition and classification of the histamine-release response to drugs in anaesthesia and surgery: studies in the conscious human subject. Klin Wochenschr 60:896–913
Lumsden T (1923) Observations on the respiratory centres. J Physiol 57:354–367
Mansour A, Fox CA, Burke S et al (1994) Mu, delta, and kappa opioid receptor mRNA expression in the rat CNS: an in situ hybridization study. J CompNeurol 350:412–438
Marone G, Stellato C, Mastronardi P et al (1993) Mechanisms of activation of human mast cells and basophils by general anesthetic drugs. Ann Fr Anesth Reanim 12:116–125
Maurer U, Kager C, Fellinger C et al (2014) Risk of anaphylaxis in opioid dependent persons: effects of heroin versus substitution substance. Subst Abuse Treat Prev Policy 9:12. https://doi.org/10.1186/1747-597X-9-12
McBride P, Jacobs R, Bradley D et al (1989) Use of plasma histamine levels to monitor cutaneous mast cell degranulation. J Allergy Clin Immunol 83:374–380
Mertes PM, Laxenaire MC, Alla F (2003) Anaphylactic and anaphylactoid reactions occurring during anesthesia in France in 1999–2000. Anesthesiology 99:536–545
Methadone and hypersensitivity (2021). http://www.ehealthme.com/ds/methadone-hydrochloride/hypersensitivity/ Accessed 20 Mar 2021
Mildh LH, Tuomisto LM, Scheinin M et al (2000) Morphine-induced cardiovascular stimulation: the effects of two doses on healthy subjects. Anesth Analg 91:51–57
Miller JR, Zuperku EJ, Stuth EAE et al (2017) A subregion of the parabrachial nucleus partially mediates respiratory rate depression from intravenous remifentanil in young and adult rabbits. Anesthesiology 127:502–514
Milojevic IA, Simic D, Markovic M et al (2009) Anaphylactic reaction during general anaesthesia associated with positive skin test to fentanyl. Anaesth Intensive Care 37:502–503
Mockenhaupt M, Viboud C, Dunant A et al (2008) Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risk with emphasis on recently marketed drugs. The EuroSCAR-Study J Invest Dermatol 128:35–44
Mohrenschlager M, Glockner A, Jessberger B et al (2000) Codeine caused pruritic scarlatiniform exanthemata: patch test negative but positive to oral provocation test. Br J Dermatol 143:663–664
Montandon G, Horner R (2014) The preBotzinger complex is essential for the respiratory depression following systemic administration of opioid analgesics. J Physiol 5926:1159–1162
Montandon G, Qin W, Liu H et al (2011) PreBötzinger complex neurokinin-1 receptor-expressing neurons mediate opioid-induced respiratory depression. J Neurosci 31:1292–1301
Montandon G, Liu H, Horner RL (2016) Contribution of the respiratory network to rhythm and motor output revealed by modulation of GIRK channels, somatostatin andneurokinin-1 receptors. Sci Rep 6:32707
Mori F, Barni S, Manfredi M et al (2015) Anaphylaxis to tramadol in a child. Pharmacology 96:256–258
Morphine sulfate. FDA (2016). FDA prescribing information. Adverse reactions. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/208603s000lbl.pdf Accessed 20 Mar 2021
Mustapic S, Radocaj T, Sanchez A et al (2010) Clinically relevant infusion rates of μ-opioid agonist remifentanil cause bradypnea in decerebrate dogs but not via direct effects in the pre-Bötzinger complex region. J Neurophysiol 103:409–418
Nasmyth PA, Stewart HC (1950) The release of histamine by opium alkaloids. J Physiol 111:19P
Nasser SMS, Ewan PW (2001) Opiate-sensitivity: clinical characteristics and the role of skin prick testing. Clin Exp Allergy 31:1014–1020
Nisijima K, Yoshino T, Yui K et al (2001) Potent serotonin (5-HT)(2A) receptor antagonists completely prevent the development of hyperthermia in an animal model of the 5-HT syndrome. Brain Res 890:23–31
Nucynta® ER (Tapentadol) (2016). FDA prescribing information. Adverse reactions. https://www.accessdata.fda.gov/drugsatfda_docs/label/2016/200533s014lbl.pdf Accessed 20 Mar 2021
Otte W, Birkenhager TK, van den Broek VWV (2003) Fatal interaction between tranylcypromine and imipramine. Eur Psychiatry 18:264–265
Parke TJ, Nandi PR, Bird KJ et al (1992) Profound hypotension following intravenous codeine phosphate. Three case reports and some recommendations. Anaesthesia 47:852–854
Pattinson KTS (2008) Opioids and the control of respiration. Br J Anaesth 100:747–758
Pérez-Peréz L, Cabanillas M, Loureiro M et al (2008) Allergic contact dermatitis due to transdermal buprenorphine. Contact Dermat 58:310–312
Pevny I, Danhauser I (1981) Anaphylaktisher schock wahrend der narkose mit positivem hauttest auf fentanyl und alloferin. Anaesthesist 30:400–404
Philbin DM, Moss J, Akins CW et al (1981) The use of H1 and H2 histamine antagonists with morphine anesthesia: a double-blind study. Anesthesiology 55:292–296
Poyhia R, Kalso E, Seppala T (1992) Pharmacodynamic interactions of oxycodone and amitriptyline in healthy volunteers. Curr Ther Res 51:739–749
Poyhia R, Hynynen M, Seppala T et al (2004) Pharmacodynamics and pharmacokinetics of high-dose oxycodone infusion during and after coronary artery by-pass grafting. J Cardiothorac Anesth 18:748–754
Radomski JW, Dursun SM, Reveley MA et al (2000) An exploratory approach to the serotonin syndrome: an update of clinical phenomenology and revised diagnostic criteria. Med Hypotheses 55:218–224
Raffa RB, Friderichs E, Reimann W et al (1993) Complementary and synergistic antinociceptive interaction between the enantiomers of tramadol. J Pharmacol Exp Ther 267:331–340
Raffa RB, Buschmann H, Christoph T et al (2012) Mechanistic and functional differentiation of tapentadol and tramadol. Expert Opin Pharmacother 13:1437–1449
Ramirez J-M, Baertsch N (2018) Defining the rhythmogenic elements of mammalian breathing. Physiology 33:302–316
Rawal N, Arnér S, Gustafsson LL et al (1987) Present state of extradural and intrathecal opioid analgesia in Sweden. A nationwide follow-up survey. Br J Anaesth 59:791–799
Ready LB, Loper KA, Nessly M et al (1991) Postoperative epidural morphine is safe on surgical wards. Anesthesiology 75:452–456
Reich A, Stander S, Szepietowski JC (2009) Drug-induced pruritus: a review. Acta Derm Venereol 89:236–244
Rickli A, Liakoni E, Hoener MC et al (2018) Opioid-induced inhibition of the human 5-HT and noradrenaline transporters in vitro: link to clinical reports of serotonin syndrome. Br J Pharmacol 175:532–543
Rodriguez A, Barranco R, Latasa M et al (2005) Generalized dermatitis due to codeine. Cross Sensitizat among Opium Alkal Cont Dermat 53:240
Romberg R, Sarton E, Teppema L et al (2003) Comparison of morphine-6-glucuronide and morphine on respiratory depressant and antinociceptive responses in wild type and mu-opioid receptor deficient mice. Br J Anaesth 91:862–870
Rook EJ, van Zanten AP, Van den Brink W et al (2006) Mast cell mediator tryptase levels after inhalation or intravenous administration of high doses pharmaceutically prepared heroin. Drug Alcohol Depend 85:185–190
Rosow CE, Moss J, Philbin DM et al (1982) Histamine release during morphine and fentanyl anesthesia. Anesthesiology 56:93–96
Rosow CE, Philbin DM, Keegan CR et al (1984) Hemodynamics and histamine release during induction with sufentanil or fentanyl. Anesthesiology 60:489–491
Rossi R, Dick W (1982) Anaphylactoid reaction to the intravenous injection of morphine hydrochloride. Anesthesist 31:463–465
Rudd RA, Seth P, David F et al (2016) Increases in drug and opioid-involved overdose deaths—United States, 2010–2015. Cent Dis Cont Prevent Morbid Mortal Week Rep 65:1445–1452
Sasseville D, Blouin MM, Beauchamp C (2011) Occupational allergic contact dermatitis caused by morphine. Cont Dermat 64:166–168
Schug SA, Zech D, Grond S (1992) Adverse effects of systemic opioid analgesics. Drug Saf 7:200–213
Schwarzacher SW, Rüb U, Deller T (2011) Neuroanatomical characteristics of the human pre-Bötzinger complex and its involvement in neurodegenerative brainstem diseases. Brain 134:24–35
Shaikh WA (1990) Allergy to heroin. Allergy 45:555–556
Shanahan EC, Marshall AG, Garrett CP (1983) Adverse reactions to intravenous codeine phosphate in children. A report of three cases. Anaesthesia 38:40–43
Shear NH (ed) (2021) Litt’s Drug eruption and reaction manual, 27th edn. CRC Press, Boca Raton
Smith JC, Ellenberger HH, Ballanyi K et al (1991) Pre-Bötzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science 254:726–729
Song G, Wang H, Xu H et al (2012) Kölliker-Fuse neurons send collateral projections to multiple hypoxia-activated and nonactivated structures in rat brainstem and spinal cord. Brain Struct Funct 217:835–858
Sonnenberg CM, Deeg DJ, Comijs HC et al (2008) Trends in antidepressant use in the older population: results from the LASA-study over a period of 10 years. J Affect Discord 111:299–305
Steffanutto TB, Wright PMC (2005) Anaphylaxis precipitated by intravenous morphine sulphate. South African Journal of Anaesthesia and Analgesia. February 36–37
Stellato C, Cirillo R, de Paulis A et al (1992) Human basophil/mast cell releasability. IX. Heterogeneity of the effects of opioids on mediator release. Anesthesiology 77:932–940
Sternbach H (1991) The serotonin syndrome. Am J Psychiatry 148:705–713
St-John WM, Paton JFR (2004) Role of pontile mechanisms in the neurogenesis of eupnea. Respir Physiol Neurobiol 143:321–332
Stucke AG, Miller JR, Prkic I et al (2015) Opioid-induced respiratory depression is only partially mediated by the preBötzinger complex in young and adult rabbits in vivo. Anesthesiology 122:1288–1298
Tacquard C, Collange O, Gomis P et al (2017) Anaesthetic hypersensitivity reactions in France between 2011 and 2012: the 10th GERAP epidemiologic survey. Acta Anaesthesiol Scand 61:290–299
Tharp MD, Kagey-Sobotka A, Fox CC (1987) Functional heterogeneity of human mast cells from different anatomic sites: in vitro responses to morphine sulfate. J Allergy Clin Immunol 79:646–653
Tzschentke TM, Christoph T, Kögel B et al (2007) (-)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol hydrochloride (tapentadol HCl ): a novel μ-opioid receptor agonist/norepinephrine reuptake inhibitor with broad-spectrum analgesic properties. J Pharmacol Exp Ther 323:265–276
Uehlinger C, Hauser C (1999) Allergic reactions from injectable methadone. Am J Psychiatry 156:973
Ultram® (Tramadol) (2017). FDA prescribing information. Adverse reactions. https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/021692s015lbl.pdf
Vander Hulst K, Parera Amer E, Jacobs C et al (2008) Allergic contact dermatitis from transdermal buprenorphine. Contact Dermatitis 59:366–369
Varga AG, Reid BT, Kieffer BL et al (2020) Differential impact of two critical respiratory centres in opioid-induced respiratory depression in awake mice. J Physiol 598:189–205
Varga AG, Maletz SN, Bateman JT et al (2021) Neurochemistry of the Kölliker-Fuse nucleus from a respiratory perspective. J Neurochem 156:16–37
Vidal C, Perez-Leiros P, Bugarin R et al (2000) Fever and urticaria to codeine. Allergy 55:416–417
Volpi DA, McMahon Tobin GA, Mellon RD et al (2011) Uniform assessment and ranking of opioid Mu receptor binding constants for selected opioid drugs. Regul Toxicol Pharmacol 59:385–390
Volpi-Abadie J, Kaye AM, Kaye AD (2013) Serotonin syndrome. The Ochsner J 13:533–540
Waclawski ER, Aldridge R (1995) Occupational dermatitis from thebaine and codeine. Cont Dermat 33:51
Waisbren BA, Smith MB (1978) Hypersensitivity to pethidine. JAMA 239:1395
Warner MA, Hosking MP, Gray JR et al (1991) Narcotic-induced histamine release: a comparison of morphine, oxymorphone, and fentanyl infusions. J Cardiothorac Vasc Anesth 5:481–484
Wen W, Lynch Y, Munera C et al (2013) Application site adverse events associated with the buprenorphine transdermal system: a pooled analysis. Expert Opin Drug Saf 12:309–319
Wheatley RG, Somerville ID, Sapsford DJ et al (1990) Post-operative hypoxaemia: Comparison of extradural, i.m. and patient-controlled analgesia. Brit J Anaesth 64:267–275
White JM, Irvine RJ (1999) Mechanisms of fatal opioid overdose. Addiction 94:961–972
Wong KC, Martin WE, Hornbein TF et al (1973) The cardiovascular effects of morphine sulfate with oxygen and with nitrous oxide in man. Anesthesiology 38:542–549
Wootton CL, English JS (2012) Occupational allergic contact dermatitis caused by oxycodone. Cont Dermat 67:383–384
Yaksh T, Wallace MS (2011) Opioids, analgesia, and pain management. In: Brunton L, Chabner B, Knollman B (eds) Goodman and Gilman’s the pharmacological basis of therapeutics. McGraw -Hill Medical, New York, pp 481–526
Yang CF, Feldman JL (2018) Efferent projections of excitatory and inhibitory preBötzinger Complex neurons. J Comp Neurol 526:1389–1402
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Baldo, B.A. Toxicities of opioid analgesics: respiratory depression, histamine release, hemodynamic changes, hypersensitivity, serotonin toxicity. Arch Toxicol 95, 2627–2642 (2021). https://doi.org/10.1007/s00204-021-03068-2
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DOI: https://doi.org/10.1007/s00204-021-03068-2