Naltrexone Metabolism and Concomitant Drug Concentrations in Chronic Pain Patients

Naltrexone is effective in treating opioid dependence by blockingm, k and d opiate receptors. Naltrexone is mainly metabolized toan active metabolite 6b-naltrexol by dihydrodiol dehydrogenaseenzymes. Concomitant opioids will not be effective while patientsare taking this antagonist. This was a retrospective analysis of urin-ary excretion data collected from patients being treated with pain be-tween November 2011 and May 2012. Naltrexone, 6b-naltrexol andconcomitant opiate concentrations were measured by liquid chroma-tography–tandem mass spectrometry. Interpatient variability wascalculated from ﬁrst-visit specimens, and intrapatient variabilitywas calculated from patients with two or more visits. Relationshipsof the metabolic ratio (MR; 6b-naltrexol/naltrexone) with age, gen-der and urinary pH were also explored. From 88 ﬁrst-visit patient spe-cimens, the median MR was 3.28 (range 0.73–17.42). The MR washigher in women than men (5.00 vs. 3.14, P < 0.05). The MR showedno association based on age and urinary pH. Eighteen of 88 patientstaking oral naltrexone tested positive for concomitant opiate use.Urinary MRs of 6b-naltrexol/naltrexone were highly variable,which may contribute to variability in efﬁcacy, toxicity and patientwillingness to take naltrexone as directed. Twenty percent ofpatients tested positive for opiates and naltrexone, thus showingthe importance of monitoring patients taking naltrexone.IntroductionPrescription drug abuse is a growing problem, and opioids areamong the classes of medications that are commonly abused.The National Institute on Drug Abuse has reported that opioidprescriptions dispensed by retail pharmacies in the USA havenearly doubled from 2000 to 2010 (1, 2). Opioids are prescribedto reduce pain but have a high abuse potential. Methadone andbuprenorphine have been successful in treating patients withopioid dependence, but their use has been restricted by policiesthat limit patients’ access to these medications (3). Another op-tion is naltrexone, which is generally well tolerated with no po-tential for addiction (4). Naltrexone is an opioid antagonist thatcantreatopioiddependencebyblockingm,kanddopioidrecep-tors and prevents the feeling of reward in opioid users (5, 6).Patients should be free of opioids for 7–10 days before startingnaltrexone to prevent withdrawal symptoms, and opioid medica-tions should not be used during treatment with naltrexone. Thebiggest concern, providers have in prescribing naltrexone, is thelow rate of patients taking the drug as prescribed, and the highrate of patients relapsing with opioid use (7).Naltrexone is metabolized through liver cystolic dihydrodioldehydrogenases into 6b-naltrexol, which is an active metabolitethat participates in the pharmacological response (5, 8). Themetabolite has a much longer half-life than the parent drug butis less potent in reducing opioid cravings (9, 10). Although theprevious studies have reported interpatient variability in themetabolism of naltrexone, the population sizes were quitesmall (8, 9, 11). Interpatient variability of naltrexone metabolismmay contribute to differences in side effects and patient adher-ence. The retention of patients on naltrexone therapy is low,and methods need to be developed to improve the likelihoodof patients taking the medication as directed (7). Detection ofnaltrexoneintheurineandmonitoringconcentrationsisimport-ant to ensure that patients are taking the medication and thusreduce the number of relapses to opioid dependence.Prior studies have analyzed cravings of patients using opioidswhile on naltrexone therapy, and patients who discontinuednaltrexone due to relapse (6, 12). However, data are limiteddocumentingthe percentage ofpatients who may be taking con-comitantopioidswhileonnaltrexonetherapy,withouttheirpre-scribers’ knowledge (7). Serious injury, adverse effects and deathhave been reported in cases of patients who used opioids con-comitantly with naltrexone, in an attemptto overcometheopioidblockade (13–15). Adverse effects of naltrexone-acceleratedopioid withdrawal may include delirium, severe vomiting anddiarrhea, tachycardia and agitation (13). Some of these patientspresenting to the emergency room were unaware that theywere taking an opioid antagonist (15).Patientsneedtofullyunderstand the risks of taking opioids while on naltrexonetherapy. One suggested approach to help decrease naltrexone-related toxicities is that patients carry a medical card in caseof emergencies, indicating they cannot receive opioids forpain (16).The previous studies have shown higher concentrations ofplasma naltrexone decreased cravings for opioids (12). Idealplasma levels of naltrexone have been studied (12), but it maybeusefultoestablishexpectedurinaryconcentrationsofnaltrex-one and 6b-naltrexol to aid in interpreting urine drug tests formonitoring. The purpose of this analysis was to observe the vari-ability in metabolic ratios (MRs), and the ranges of concentrationprescribers canexpectintheurineofpatientstakingnaltrexone.Theeffectsofvariablessuchaspatientage,sexandurinarypHonmetabolism were explored, and prevalence rates of subjects tak-ing concurrent opioids and naltrexone were analyzed.ExperimentalData collection of urine specimensThis retrospective data analysis included urine specimens col-lected from routine clinical testing of patients with chronicpain between November 2011 and May 2012. Specimens were