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Anesth Pain Med. 2014 December; 4(5): e20990. DOI: 10.5812/aapm.20990 Case Report Published online 2014 1RYHPEHU 14.

“Robo-Tripping”: Abuse and its Implications

1 1 1,* Kelly A Linn ; Micah T Long ; Paul S Pagel

1Anesthesia Service, Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, USA *Corresponding author : Paul S Pagel, Anesthesia Service, the Clement J. Zablocki Veterans Affairs Medical Center, Milwaukee, Wisconsin, 53295, USA. Tel: +1-4143842000; Fax: 1-4143842939, E-mail: [email protected] Received: ; Revised: ; Accepted: June 6, 2014 June 29, 2014 July 6, 2014

Introduction: We describe a patient scheduled for elective surgery who regularly consumed approximately 12 to 15 times the maximum recommended daily dose of dextromethorphan. We describe the clinical of dextromethorphan and discuss its anesthetic implications. Case Presentation: A 30-year-old man with a history of a nasal fracture was scheduled to undergo an elective septorhinoplasty. He reported daily consumption of large quantities (1440 to 1800 mg) of dextromethorphan for six years. He was previously treated for dextromethorphan dependency on several occasions with dextromethorphan levels exceeding 2000 ng/mL. He described marked effects when abusing the , but had abstained from use for 48 hours before his elective surgery. Considering that dextromethorphan has a relatively short half-life and that the patient did not suffer major withdrawal symptoms after voluntarily discontinuing the drug, the authors proceeded with the case while recognizing that the drug has significant neuropsychiatric and sympathetic nervous system effects resulting from its actions as a N-methyl-D-aspartate antagonist. Conclusions: Anesthesiologists need to be aware of dextromethorphan’s clinical pharmacology because recreational abuse of the drug has become increasingly common in adolescents and young adults. Keywords: Dextromethorphan; Sigma Receptor; ; ; Dissociative Anesthesia; NMDA Receptor

Antagonists

1. Introduction

Dextromethorphan is widely available antitussive medi- daily dose of dextromethorphan. We describe the phar- cation that is a major component of more than 140 macology of dextromethorphan and discuss the anesthet- and cough remedies sold over the counter (1, 2). The drug ic implications of this drug of abuse. The patient’s written is a D- of the opioid consent was obtained for publication of this report. and may exert its antitussive effects by activating sigma1 2. Case Presentation opioid receptors in the medullary cough center. Recom- mended doses of dextromethorphan (maximum of 120 A 30-year-old, 116 kg, 180 cm man with a history of symp- mg in four divided doses per day) are often associated tomatic persistent nasal congestion after a nasal fracture with a dry mouth, , and a reduced ability to was scheduled to undergo an elective septorhinoplasty. concentrate resulting from a mild effect, His was notable for insulin depen- but acute ingestion of larger doses causes a dissociative dent diabetes mellitus, essential hypertension treated state similar to that observed with and with lisinopril, use, and depression. He also de- (1, 3, 4) because the drug’s primary metabolite scribed a history of and abuse. The is a putative N-methyl-D-aspartate (NMDA) receptor an- patient reported that he abstained from using these tagonist (5, 6). This latter pharmacological action, com- substances during the previous ten months, but he did bined with easy access to the drug, has contributed to an admit that he was consuming large quantities [1440 to increase in the recreational abuse of dextromethorphan- 1800 mg per day (between 48 and 60 tablets)] of dex- containing formulations in adolescents and young adults tromethorphan on a daily basis for the past six years. (7, 8) sometimes termed “robo-ing”, “robo-copping”, or He obtained the dextromethorphan from a local phar- “robo-tripping” after the popular cough syrup Robitus- macy. He had been treated in our institution for dextro- sin DM® (Pfizer, Kings Mountain, , USA) (9, detoxification and dependency on several 10). In this report, we describe a young man scheduled for occasions, most recently one month before the planned an elective septorhinoplasty who regularly consumed ap- septorhinoplasty. Urine dextromethorphan levels were proximately 12 to 15 times the maximum recommended greater than 2000 ng/mL during the patient’s detoxifi-

Copyright © 2014, Iranian Society of Regional Anesthesia and Pain Medicine (ISRAPM); Published by Kowsar. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/) which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited. KA Linn et al. cation admissions. The patient stated that dextrometho- The peak plasma concentration and the usual duration rphan gave him “dumb and numb” feelings so that he of clinical effect are 2.5 and 6 hours, respectively, after “did not have to think [about] problems.” He described ingestion of the drug (4, 17). Dextromethorphan is rap- marked fatigue and depressed mood on days that he idly metabolized to by hepatic cytochrome did not ingest dextromethorphan, but he denied physi- P450 2D6 in most subjects with a plasma half-life of 2 to 4 cal signs and symptoms of . The patient hours, but approximately 5% of individuals of northern stated that he voluntarily did not use dextromethorphan European extraction have a deficiency of this during the previous 48 hours in anticipation of his elec- that may cause rapid accumulation of the parent drug tive surgery. The patient’s wife supported this assertion. (5). This specific pharmacokinetic polymorphism ren- The physical examination and laboratory findings were ders the subset of individuals substantially more suscep- unremarkable. The function tests were normal. A tible to drug toxicity (17). random urine drug screen performed one month before The neuropsychiatric and sympathetic nervous sys- surgery was negative for ethanol, , barbi- tem effects of dextromethorphan are dose-related (1, turates, , metabolites, and opi- 3, 4). Trance-like or stupor, hyperexcitability, oids. We did not obtain a urine drug screen on the day , altered mental status, dyskinesia, of surgery because routine drug testing does not detect delayed response times, disordered speech, and vivid dextromethorphan (1) and the patient was not displaying auditory and visual occur as the ingested signs and symptoms of acute intoxication with dextro- dose of dextromethorphan increases above 2 mg/kg (1, methorphan or other of abuse. 3). Indeed, the current patient described a dissociative Considering that dextromethorphan has a relatively stupor and depersonalization when he was abusing short half-life (4) and that the patient had not suffered dextromethorphan. Respiratory depression, tachycar- any withdrawal symptoms after discontinuing the drug, dia, hypertension, , and may result from the authors elected to proceed with the case and the pa- severe acute dextromethorphan intoxication (1, 4, 7, 8, tient was transported to the operating room. Anesthesia 16) whereas chronic abuse of the drug has been associ- was induced using (2 mg/kg), (1 mg/ ated with frank psychosis (2). These actions are very kg), (1.5 mg/kg), and rocuronium (0.6 mg/kg) similar to those described with other NMDA receptor and maintained using sevoflurane (end-tidal concen- antagonists. Thus, it appears likely that the anesthetic trations of 1.5 to 2% in an air-oxygen mixture; fractional implications of acute dextromethorphan abuse may be inspired oxygen concentration of 0.5), fentanyl (1.5 mg/ quite similar those associated with abuse of ketamine kg), and (0.2 mg) after endotracheal in- or phencyclidine, but at present, no data have been - tubation. The patient’s vital signs remained within 20% of lished to verify this contention. The concomitant pres- baseline levels throughout the case. He was extubated in ence of or sympathomimetic drugs in the operating room at the end of case. Postoperative pain common cough and cold formulations may influence was treated using intravenous hydromorphone (1.2 mg the clinical manifestations of dextromethorphan abuse in divided doses) in the postanesthesia care unit and was (4). In addition to NMDA activ- subsequently managed using oral with ac- ity, dextromethorphan and its metabolite dextrorphan etaminophen after the patient was discharged from the are specific reuptake inhibitors (SSRI) (2). As hospital later that day. He reported excellent pain control a result, acute intoxication of dextromethorphan has (visual analog scale of 3/10) when he was seen in the oto- been linked to serotonin syndrome, particularly when laryngology clinic for routine follow-up on the 3rd post- the drug is ingested in the presence of another SSRI or a operative day. The remainder of his postoperative course serotonergic [e.g. such as buspirone was unremarkable. ( or depression); triptans including sumatriptin 3. Discussion (migraine or cluster headaches)]. Dextromethorphan abuse is particularly likely to cause serotonin syndrome Descriptions of recreational dextromethorphan abuse in patients treated with the SSRI antidepressant medi- have appeared in the peer-reviewed medical literature cation because the latter drug also inhibits 450 with increasing frequency (4, 7, 10-12) since the phenom- cytochrome P 2D6 activity. enon was first reported in Europe in the mid-1960s (13, Dextromethorphan is often combined with the chlor- 14). A recent survey of the National Poison Data System phenamine in many commercially available cough and quantified the incidence of dextromethorphan abuse cold preparations (e.g. Coricidin®, Schering-Plough, in the as 15.7 cases per 1 million citizens Kenilworth, New Jersey, USA). This exerts (8), but dextromethorphan abuse has not been previ- serotonergic effects independent of dextromethorphan, ously documented in (15). The drug is particularly and abuse of this combined formulation further in- popular among teenagers and young adults because it is creases the risk that serotonin syndrome may develop unregulated, inexpensive or easily stolen from retailers, (18). Serotonin syndrome has also been reported with readily obtained from a variety of commercial sources ingestion of dextromethorphan alone (19) via NMDA including the internet, and consumed orally (1, 2, 4, 16). antagonist-mediated 5-HT2A receptor activation (20). Se-

2 Anesth Pain Med. 2014;4(5):e20990 KA Linn et al. rotonin toxicity may contribute to hyperreflexia, muscle patient, benzodiazepines were not administered for con- rigidity, and autonomic nervous system instability (21) scious sedation or during anesthetic induction because observed when large doses of dextromethorphan are these drugs may delay discharge in patients undergoing consumed. Finally, polysubstance abuse is very common ambulatory surgery. The patient also had abstained from among dextromethorphan users (3), and simultaneous abusing dextromethorphan in anticipation of elective use of other drugs may certainly affect the overall clini- surgery and did not display clinical signs or symptoms cal presentation of dextromethorphan toxicity. Abuse of acute dextromethorphan intoxication. Thus, the use of of dextromethorphan with or cocaine benzodiazepines was not directly indicated based solely may also increase the risk of serotonin syndrome. Nota- on the consequences of acute dextromethorphan intoxi- bly, the risk of an unfavorable outcome is substantially cation, in the authors’ opinion. It is also unclear whether greater when dextromethorphan is abused with other the sigma1-opioid agonist and NMDA receptor antago- illicit substances (4). nist properties of acute or chronic dextromethorphan Unlike our patient who openly admitted and had been abuse affect perioperative opioid requirements. Our previously treated for long standing abuse of dextro- patient’s postoperative pain after septorhinoplasty was methorphan, the diagnosis of acute or chronic dextro- easily managed using conventional doses of intravenous methorphan abuse most likely requires a high index of followed by oral despite his history of chronic suspicion, but may be suggested with a carefully con- dextromethorphan abuse, suggesting that clinically sig- ducted history and physical examination in the periop- nificant opioid tolerance did not occur. Finally, whether erative setting. Patients with acute dextromethorphan acute dextromethorphan intoxication is capable of re- intoxication commonly exhibit signs and symptoms ducing opioid requirements during and after surgery similar to those associated with stimulant, phencycli- similar to subanesthetic doses of ketamine also remains dine, or ketamine abuse, and exclusion of these more to be established. common abused drugs using a urine drug screen may Management of dextromethorphan toxicity is almost indirectly infer a diagnosis of dextromethorphan abuse. entirely supportive because there is no known Indeed, routine drug screening does not detect dextro- for the drug. Three case reports described the use of the methorphan when recommended doses are ingested nonselective to reverse dex- (1), but false positive results suggesting the presence of tromethorphan-induced respiratory depression (11, 25, phencyclidine or opioids may sometimes be observed 26), but the relative value of naloxone for the treatment when large quantities of the drug are consumed (22). of other manifestations of dextromethorphan toxicity High performance liquid chromatography is required to remains unclear (1). Another report suggested that pro- quantify plasma dextromethorphan concentration (5). pofol may be useful for the management of acute dex- As observed in the current patient, other laboratory tests tromethorphan intoxication complicated by serotonin are most often noncontributory in patients with acute syndrome (19). These observations are intriguing, but the or chronic dextromethorphan intoxication. Prolonged precise implications of these reports (11, 19, 25, 26) on the QT interval has been previously reported in acute dextro- perioperative management of the acute or chronic dex- methorphan intoxication (23), but this abnormality was tromethorphan abuser undergoing emergent or elective not observed in our patient’s electrocardiograms during surgery are currently unknown. Chronic dextrometho- his detoxification admissions. rphan abusers may suffer from symptoms of psychologi- The specific anesthetic implications of acute or chronic cal withdrawal (2, 3, 12). Indeed, our patient described dextromethorphan abuse have not been described in the pronounced fatigue and depressed mood immediately peer-reviewed literature to date. Considering that sym- after discontinuing dextromethorphan use. Such indi- pathetic nervous system stimulation is a characteristic viduals may benefit from admission for detoxification feature of dextromethorphan toxicity (as it is with other and substance abuse treatment with the goal of attain- NMDA receptor antagonists including phencyclidine ing abstinence from the drug before elective surgery is and ketamine) (24), it would appear likely that adminis- contemplated. tration of vasoactive drugs, including intravenous and Authors’ Contributions volatile , should be approached with caution in dextromethorphan abusers because of the potential Kelly A. Linn cared for the patient for the patient in the for hemodynamically significant drug interactions. This operating room and wrote drafts of the manuscript. The hypothesis has yet to be formally examined to date. As is author has read the final draft of the manuscript and the case with the generalized neuroexcitation associated approves it for submission. Micah T. Long cared for the with abuse of other NMDA receptor antagonists, dextro- patient for the patient in the operating room and wrote methorphan-induced agitation, delusions, and halluci- drafts of the manuscript. The author has read the final nations may theoretically be mitigated using benzodiaz- draft of the manuscript and approves it for submission. epines before surgery. Nevertheless, the relative efficacy Paul S. Pagel wrote and edited drafts of the manuscript. of benzodiazepines in such a perioperative application The author has read the final draft of the manuscript and has not been specifically documented. In the current approves it for submission.

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Funding/Support 13. Degkwitz R. [Dextromethorphan (Romilar) as an Intoxicating Nervenarzt. 35 Agent]. 1964; :412–4. Ugeskr Laeger. 14. Jorgensen F. [Abuse of dextromethorphan]. This work was supported entirely by departmental funds. 129 1967; (36):1148–50. References 15. Sahraian A, Sharifian M, Omidvar B, Javadpour A. Prevalence of substance abuse among the medical students in Southern Iran. Clin Pedi- Shiraz E Med J. 11 1. Schwartz RH. Adolescent abuse of dextromethorphan. 2010; (4):198–202. atr (Phila). 44 2005; (7):565–8. 16. Logan BK, Goldfogel G, Hamilton R, Kuhlman J. Five re- 2. Miller SC. Dextromethorphan psychosis, dependence and physi- sulting from abuse of dextromethorphan sold over the internet. Addict Biol. 10 J Anal Toxicol. 33 cal withdrawal. 2005; (4):325–7. 2009; (2):99–103. 3. Ziaee V, Akbari Hamed E, Hoshmand A, Amini H, Kebriaeizadeh A, 17. Bem JL, Peck R. Dextromethorphan. An overview of safety issues. Drug Saf. 7 Saman K. Side effects of dextromethorphan abuse, a case series. 1992; (3):190–9. Addict Behav. 30 2005; (8):1607–13. 18. Monte AA, Chuang R, Bodmer M. Dextromethorphan, chlorphen- 4. Romanelli F, Smith KM. Dextromethorphan abuse: clinical effects amine and serotonin toxicity: case report and systematic litera- J Am Pharm Assoc (2003). 49 Br J Clin Pharmacol. 70 and management. 2009; (2):e20–5. ture review. 2010; (6):794–8. 5. Silvasti M, Karttunen P, Tukiainen H, Kokkonen P, Hanninen U, 19. Ganetsky M, Babu KM, Boyer EW. Serotonin syndrome in dextro- Pediatr Nykanen S. of dextromethorphan and dex- methorphan ingestion responsive to propofol therapy. Emerg Care. 23 trorphan: a single dose comparison of three preparations in hu- 2007; (11):829–31. Int J Clin Pharmacol Ther Toxicol. 25 man volunteers. 1987; (9):493–7. 20. Kim HS, Park IS, Lim HK, Choi HS. NMDA receptor antagonists en- 6. Szekely JI, Sharpe LG, Jaffe JH. Induction of phencyclidine-like be- hance 5-HT2 receptor-mediated behavior, head-twitch response, Phar- Arch Pharm Res. 22 havior in rats by dextrorphan but not dextromethorphan. in PCPA-treated mice. 1999; (2):113–8. macol Biochem Behav. 40 N Engl J Med. 1991; (2):381–6. 21. Boyer EW, Shannon M. The serotonin syndrome. 352 7. Murray S, Brewerton T. Abuse of over-the-counter dextrometho- 2005; (11):1112–20. South Med J. 86 rphan by teenagers. 1993; (10):1151–3. 22. Banerji S, Anderson IB. Abuse of Coricidin HBP cough & cold tab- Am J Health Syst Pharm. 8. Wilson MD, Ferguson RW, Mazer ME, Litovitz TL. Monitoring lets: episodes recorded by a poison center. 58 trends in dextromethorphan abuse using the National Poison 2001; (19):1811–4. Clin Toxicol (Phila). 49 Data System: 2000-2010. 2011; (5):409–15. 23. Kaplan B, Buchanan J, Krantz MJ. QTc prolongation due to dextro- Int J Cardiol. 148 9. Darboe MN. Abuse of dextromethorphan-based cough syrup as methorphan. 2011; (3):363–4. a substitute for licit and illicit drugs: a theoretical framework. 24. Pagel PS, May JA. Evaluation of the patient with or drug Adolescence. 31 1996; (121):239–45. addiction. In: Longnecker D, Brown DL, Newman MF, Zapol W Anesthesiology. 10. Darboe MN, Keenan GR, Jr, Richards TK. The abuse of dextro- editors. 2 ed. New York: McGraw-Hill Education; methorphan-based cough syrup: a pilot study of the community 2012. pp. 315–31. Adolescence. 31 of Waynesboro, . 1996; (123):633–44. 25. Shaul WL, Wandell M, Robertson WO. Dextromethorphan toxic- N Engl J Med. Pediatrics. 59 11. Katona B, Wason S. Dextromethorphan danger. ity: reversal by naloxone. 1977; (1):117–8. 314 1986; (15):993. 26. Schneider SM, Michelson EA, Boucek CD, Ilkhanipour K. Dextro- J Am Acad Am J Emerg Med. 12. Miller SC. Coricidin HBP cough and cold addiction. methorphan poisoning reversed by naloxone. Child Adolesc Psychiatry. 44 9 2005; (6):509–10. 1991; (3):237–8.

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