Although the abuse potential of remifentanil has been acknowledged,1 it has been widely used in clinical practice for a number of years without a single reported incident of abuse. A number of animal studies have shown the potential for remifentanil abuse,2–4 but the relative complexity required for self-administration of the IV form of the drug makes this route impractical. After an extensive literature search involving 1870 articles, we were unable to find any published reports of remifentanil abuse. Herein, we report a documented case of remifentanil abuse by an anesthesiology resident.
A 36-yr-old male resident in his third year of clinical anesthesia training with no history of substance abuse was reported to the impaired physicians committee for evaluation after several instances of abnormal behavior. A number of attending physicians had observed the resident as chronically diaphoretic, having erratic behavior, and requiring extended breaks during clinical cases. On return to the operating room from these breaks, the resident was noted to have facial pruritus and nasal discharge. The resident was confronted and he initially denied any diversion of opioids for personal use. He was informed that he would be suspended from clinical duties pending further investigation, and a urine sample was obtained for analysis. On further questioning, he admitted to IV administration of fentanyl, which he had begun using several weeks prior. He reported that he initially began to divert remifentanil, which he insufflated nasally in the nonreconstituted lyophilized solid form, but discontinued this practice because of intense nausea and withdrawal symptoms. Because he acquired a dependence for opioid intoxication, he began to use fentanyl IV. After identification, the resident was referred to the state medical society physician health program and admitted into an inpatient rehabilitation program.
Even though the anilidopiperidine opioid remifentanil has pharmacodynamic properties similar to all opioids, its unique pharmacokinetic characteristics make it an unlikely choice among opioids with abuse potential. It is short acting because of metabolism by widespread esterases found throughout the plasma, red blood cells, and interstitial tissues, and its context-sensitive half-time is 3–4 min regardless of the duration of infusion.5 Although synthetic opioids have been administered transmucosally,6 there are few data on the pharmacokinetics of transnasal remifentanil and no information on the impact of remifentanil's pharmacokinetics when administered in the nonreconstituted form. From the work in children, it can be surmised that reconstituted transnasal remifentanil has a slower onset, requires larger doses for desired effect, and has a longer duration of action (although still exceedingly short) compared with IV remifentanil.6 In this study, the peak effect occurred 3.47 min after administration. In addition, it has been speculated that patients receiving IV remifentanil develop tolerance during administration.7 In regard to the addiction liability of remifentanil, the rapid onset and variable quantity of unreconstituted powder obtainable from a vial pose a danger of overdose, whereas the rapid termination of effects and development of tolerance are likely to lead to the abuse of IV fentanyl and other longer-acting drugs.
The need to use cumbersome infusion equipment to safely maintain clinically relevant levels of drug has likely contributed to the absence of reported abuse of this drug despite its classification as “an opioid narcotic with an addiction-forming and addiction-sustaining liability similar to morphine.”8 In fact, an article published in 2005 identified fentanyl and sufentanil as the top drugs of abuse by anesthesiologists entering treatment for addiction but did not report any instances of remifentanil abuse.9 Baylon et al.10 examined the comparative abuse liability of fentanyl and remifentanil and could not completely exclude the possibility for remifentanil abuse by some individuals, despite the significantly higher preference for fentanyl. Their conclusions suggested that those addicts who are able to obtain both the drug and the infusion equipment might abuse remifentanil IV, but no mention was made of the possibility of intranasal ingestion. The present case clearly indicates that remifentanil has abuse potential per se and, more importantly, that it may lead to escalation and abuse of other opioids.
Although this is the first reported case of remifentanil abuse, this behavior may in fact be more prevalent than is suspected because of underreporting. Our case indicates the need for awareness of the possibility for remifentanil abuse and the need for education about the dangers or remifentanil “experimentation” among health care workers. Although remifentanil may have a low long-term abuse potential, this case illustrates that it has a high addiction potential that may lead to the use of IV longer-acting drugs. Because remifentanil has to be reconstituted for infusion, returning the unused portion of the drug to the pharmacy is cumbersome and in the past has been a point of contention at our institution. In addition, remifentanil is available in 1, 2, and 5 mg ampoules. Diverting small amounts of unreconstituted remifentanil before its reconstitution into recommended concentrations of 25, 50, or 100 μg/mL would be very difficult to detect, given the limitations of current opioid assays. While it is easy to account for the unreconstituted, unopened vials, it is just as important, although potentially difficult, to account for the unused portion of the reconstituted drug. Because hospital pharmacies may perceive remifentanil as a drug that has a low abuse potential, human and technical resources may not be allocated to monitor its use and return, as was the case with propofol before the increased awareness of the abuse potential of this drug.
We hope that publishing our experience will increase awareness of the danger of being permissive with remifentanil accounting. A major contributing cause of addiction in anesthesia is easy access to opioids and other psychoactive substances.11 As such, accounting procedures relevant to all schedule II drugs should be strictly observed, and all remifentanil waste must be returned to the pharmacy where it can be analyzed on a random basis to verify content. These tighter controls may serve as a deterrent to diversion and allow for earlier detection and documentation in suspected cases of abuse.
1. Skulska A, Kala M. Consequences of medical and non-medical use of atropine and fentanyl analogues. Z Zagadnien Nauk Sadowych 2007;71:303–12
2. Woolverton WL, Wang Z, Vasterling T, Tallarida R. Self-administration of cocaine-remifentanil mixtures by monkeys: an isobolographic analysis. Psychopharmacology 2008;198:387–94
3. Wade-Galuska T, Winger G, Woods JH. A behavioral economic analysis of cocaine and remifentanil self-administration in rhesus monkeys. Psychopharmacology 2007;194:563–72
4. Crespo JA, Panlilio LV, Schindler LW, Sturm K, Saria A, Zerning G. Peri-response pharmacokinetics of remifentanil during a self-administration session indicates that neither blood nor brain levels are titrated. Ann N Y Acad Sci 2006;1074:497–504
5. Michelsen LG, Hug CC Jr. The pharmacokinetics of remifentanil. J Clin Anesth 1996;8:679–82
6. Verghese ST, Hannallah RS, Brennan M, Yarvitz JL, Hummer KA, Patel KM, He J, McCarter R. The effect of intranasal administration of remifentanil on intubating conditions and airway response after sevoflurane induction of anesthesia in children. Anesth Analg 2008;107:1176–81
7. Guignard B, Bossard AE, Coste C, Sessler DI, Lebrault C, Alfonsi P, Fletcher D, Chauvin M. Acute opioid tolerance: intraoperative remifentanil increases postoperative pain and morphine requirement. Anesthesiology 2000;93:409–17
8. WHO Pharmaceuticals Newsletter1997, No. 03&04. UMC: WHO, 1997:15
9. Kintz P, Villain M, Dumestre V, Cirimele V. Evidence of addiction by anesthesiologists as documented by hair analysis. Forensic Sci Int 2005;153:81–4
10. Baylon GJ, Kaplan HL, Somer G, Busto UE, Sellers EM. Comparative abuse liability of intravenously administered remifentanil and fentanyl. J Clin Psychopharmacol 2000;20:597–606
11. Bryson EO, Silverstein JH. Addiction and substance abuse in anesthesiology. Anesthesiology 2008;109:905–17