Laboratory monitoring supports compliance with medically assisted opioid addiction treatment using buprenorphine
By H. Roma Levy, MS
Worldwide opioid addiction has increased dramatically in the past decade, with the greatest rise documented in the United States.1–3 A primary factor driving this growth was the increasing use of prescription opioids (eg, hydrocodone, morphine, and oxycodone) for chronic pain in response to the American Pain Society’s recommendation that pain should be assessed as the ‘fifth vital sign’ in outpatient care.4,5
Recreational use of heroin also continues to contribute to opioid addiction. In the United States alone, heroin use among people aged 12 years or older almost doubled between 2002 and 2014, rising from 1.6 per 1000 persons to 2.6 per 1000 persons. Illegally obtained prescription opioids serving as gateway drugs account for approximately 80% of this population.2 Conversely, previous heroin use underlies only 20% of prescription opioid abuse.2
Opioid Chemistry and Physiologic Effects
Opioid drugs are derived from the opium poppy, Papaver somniferum. First cultivated by the Sumerians and named ‘hul gil’ (the joy plant), opium and derivative drugs have been used for over five millennia, both medically (analgesia, sedation) and recreationally (euphoria).6 Naturally derived and semisynthetic opioids share a similar structure, while synthetic opioids do not (Figure 1).7 Their primary agonist targets are µ (mu) receptors. These drugs can also cause depressed respiration, slowed or rapid heart rate, and reduced gastric motility.7 Due to cardiopulmonary effects, overdose can be fatal.
All opioid effects are in response to drug stimulation of µ receptors, which are found in the brain, spinal cord, and gastrointestinal tract. The natural µ receptor agonist is ß-endorphin (‘endogenous morphine’), a 31-amino acid neuropeptide/neurohormone.8 When released in the central nervous system, ß-endorphin interacts with the mesolimbic reward system. This system uses positive reward to reinforce learning and behavior necessary for survival.
When ß-endorphin activates µ receptors in response to enjoyable input, dopamine is released and stimulates specific brain loci. Some of these loci trigger sensations of pleasure and desire, while others evaluate the benefit of repeating the behavior. When it interacts with synapses in the peripheral nervous system, ß-endorphin acts as a natural pain killer. Feeling ‘normal’ depends on regular low-level stimulation of peripheral nervous system µ receptors by ß-endorphin; without such stimulation, even a minor injury such as a stubbed toe would register as incapacitating pain.8–10
Hijack of central nervous system and peripheral nervous system µ receptor functions by either prescription or illicit opioids can cause addictive behavior in genetically and environmentally susceptible individuals.9 Opioid addiction includes both physiologic drug dependence (drug is needed to replace non-pain-related peripheral nervous system stimulation by ß-endorphin) and physical and psychological cravings (central nervous system loci associated with cravings and reward value require constant stimulation). Tolerance develops with continued drug use, requiring ever-increasing dosage to achieve both euphoric effects and feelings of physical normalcy.
Because most opioid drugs are short-acting, with effects lasting from only a few hours to 8 hours, addicted users cycle repeatedly through peaks of physical well-being and valleys of minor to severe withdrawal symptoms.7,11 Continued use of opioids—especially pharmaceutical-grade opioids—can result in changes to brain chemistry and morphology, resulting in down-regulation of ß-endorphin synthesis and increasing or total dependence on exogenous drugs.9,12
Medically Assisted Therapy for Opioid Addiction
Because of the damage it causes to normal endorphin-producing cells, opioid addiction is considered a chronic brain disease that may require lifelong drug treatment and management.13 Medically assisted therapy uses drugs such as buprenorphine (BUP) to prevent the negative symptoms of withdrawal, and to ease dependency and cravings until normal brain chemistry is restored, if possible.13–15 Medically assisted therapy is a more effective option for treating addiction than methods that do not employ medication.11,16
BUP is derived from the natural opium alkaloid thebaine (Figure 2). As a partial µ agonist, BUP has high affinity for the µ receptor, preferentially binding to it over other opioids.11,17 It both displaces other opioids bound by receptors and prevents new molecules from binding (Figure 2). Because it has low physiological activity, euphoric effects are minimized when taken as intended (Table 1).7,15,18,19 The ‘high’ associated with other opioids diminishes rapidly with repeated administration of sublingual or transdermal BUP and cannot be induced by taking increasing doses when administered correctly (ceiling effect).18 This ceiling effect also reduces the risk of respiratory depression, bradycardia, and overdose.15
Despite such benefits, BUP itself is subject to abuse through diversion (circumvention) of the drug’s appropriate use. Diversion includes inappropriate drug administration (inhaling, smoking, or injection), selling prescribed pills to purchase other opioids (potentially because the treatment dose is insufficient, especially in early treatment), and skipping doses to take other opioids.1,5,20,21 Other predominant reasons include sharing prescriptions with others who don’t have access to care and are trying to self-treat, hoarding pills to use at a higher dosage, and selling a portion of the prescription to finance addiction treatment costs.5,21–24 BUP combined with naloxone (trade name Suboxone) reduces—but does not eliminate—diversion risk by inhalation or injection because administration of naloxone by these methods causes immediate and severe withdrawal symptoms.22,23
Buprenorphine urine testing is valuable both clinically and in the emergency department when screening for abused substances. The American Society of Addiction Medicine recommends urine drug testing throughout medically assisted therapy to assess compliance and promote long-term recovery; more frequent testing is suggested during early treatment and if the patient relapses.11,14,25,26 Patients treated in opioid treatment programs must be administered at least eight drug tests annually according to US federal law, but no recommendations exist for treatment through a private physician’s office. Oral BUP is prescribed both on- and off-label for chronic pain control in many countries, and periodic random monitoring is also suggested.26–28
Because of their low cost, easy accessibility, and high throughput, immunoassays are useful for primary screening. Urine concentration of BUP may be below the detection limit of most assays, therefore assays are designed to detect BUP and at least one of its three major metabolites: buprenorphine glucuronide (BUP-G), norbuprenorphine (norBUP), and norbuprenorphine glucuronide (norBUP-G). These metabolites are typically excreted in urine at concentrations many times greater than the parent drug (Figure 3; Table 2).25,29–34 Furthermore, urinary levels of the parent drug can decline appreciably in a matter of hours, which can make identification difficult in an emergent situation.
However, all three BUP metabolites can be detected in the absence of BUP, and they remain detectable for at least 4 days after sublingual administration (Figure 4).30,32–35 Gas chromatography or liquid chromatography followed by tandem mass spectrometry (MS/MS) is used to confirm immunoassay results and to determine the ratio of NorBUP:BUP as an indicator of sample adulteration (addition of crushed BUP).25,36
Assays on the Market
The Siemens Healthineers Syva Emit II Plus buprenorphine assay for Viva drug testing systems detects both BUP and norBUP. Results can be reported both qualitatively and semiquantitatively based on a 5 ng/mL cut-off.37 For both usages, positive agreement between the assay and liquid chromatography–MS/MS is 90%, and negative agreement is 98%.
Four other commercial BUP immunoassays are currently available. All four can be used either qualitatively or semiquantitatively, and all show good positive and negative agreement with tandem mass spectrometry, according to their package inserts (Table 3).38–41 The Siemens Healthineers assay performs at least comparably to all of these assays with respect to positive and negative agreement with tandem mass spectrometry, and its detection cutoff is lower than either the Lin-Zhi enzyme immunoassay or Thermo Fisher’s cloned enzyme donor immunoassay, CEDIA Buprenorphine II. Although positive agreement with liquid chromatography–MS/MS is lower for the Siemens Healthineers assay than reported by other manufacturers, this is because Siemens chose to challenge the assay by testing many samples in which the BUP concentration was very close to the 5 ng/mL cutoff.
Because of the structural similarity between BUP and other opioids, high antibody specificity for BUP and its metabolites is necessary to reduce the likelihood of false-positive results. In testing, 22 common opioids and metabolites demonstrated less than 0.01% crossreactivity with the Siemens Healthineers Emit assay at a concentration of 100,000 ng/mL. In addition, a wide range of structurally unrelated compounds and over-the-counter medications did not interfere with assay results above the 5 ng/mL cutoff.
By contrast, several independent evaluations of the original CEDIA assay conducted between 2005 and 2014, including information reported by the manufacturer, indicated up to 40% crossreactivity with other opioids and structurally dissimilar and unrelated drugs at therapeutic levels (eg, the antimalarial/immune modulators chloroquine and hydroxychloroquine, and the antipsychotics sulpride and amisulpride).31,33,42–45 Detection of these compounds generated false-positive results above the 5 ng/mL cutoff. While specificity of the CEDIA Buprenorphine II assay has improved, it has come at the expense of sensitivity. The cutoff for the updated assay has been increased to 10 ng/mL.41
A head-to-head comparison study was conducted between the Siemens Healthineers Emit and Immunalysis homogeneous enzyme immunoassays (Table 4). Overall agreement was 92%. Negative agreement was 100% when compared both qualitatively and semiquantitatively. Positive agreement was lower, at 87%, due to eight discordant samples that were negative according to the Siemens Healthineers assay and positive according to the homogeneous enzyme immunoassays. Upon further analysis using isotope dilution liquid chromatography–MS/MS, all eight samples were found to be negative and therefore in agreement with the results obtained with the Siemens Healthineers assay (Table 5). It is possible that this difference reflects slightly higher crossreactivity for norBUP by the Siemens Healthineers assay. Regardless, these data suggest that the Siemens Healthineers assay performs at least as well as the Immunalysis assay.
The opioid epidemic presents an ongoing worldwide health crisis. Opioid addiction is difficult to overcome without the aid of medically assisted therapy. Buprenorphine is a partial µ agonist used in medically assisted therapy, and random periodic urine testing is recommended to assess compliance and correct dosing.
Buprenorphine immunoassays provide only a preliminary analytical test result. A more specific alternative chemical method must be used to obtain a confirmed analytical result. Gas chromatography–tandem mass spectrometry or liquid chromatography–tandem mass spectrometry are the preferred confirmatory methods.
Immunoassays should be able to detect buprenorphine and some combination of its metabolites at a sensitivity that shows good positive agreement with mass spectrometry. Immunoassays should be highly specific to reduce false positives resulting from crossreactivity with other structurally similar opioids and structurally dissimilar non-opioid drugs that might be taken during therapy.
The Siemens Healthineers Emit II Plus buprenorphine assay is both sensitive and specific, and demonstrates good positive and negative agreement with liquid chromatography–MS/MS and the Immunalysis homogeneous enzyme immunoassay.
H. Roma Levy, MS, is a medical writer at Siemens Healthineers. For further information, contact CLP chief editor Steve Halasey via [email protected].
- World Drug Report, 2016. New York City: United Nations Office on Drugs and Crime, 2016. Available at: www.unodc.org/wdr2016. Accessed April 24, 2019.
- Jones CM, Logan J, Gladden RM, Bohm MK. Vital signs: demographic and substance use trends among heroin users; United States, 2002–2013. MMWR Morb Mortal Wkly Rep. 2015;64(26):719–725.
- Rudd RA, Seth P, David F, Scholl L. Increases in drug and opioid-involved overdose deaths; United States, 2010–2015. MMWR Morb Mortal Wkly Rep. 2016;65(50-51):1445–1452.
- Joint Commission on Accreditation of Healthcare Organizations, National Pharmaceutical Council. Pain: Current Understanding of Assessment, Management, and Treatments. Washington, DC: National Pharmaceutical Council, 2001. Available at: www.npcnow.org/publication/pain-current-understanding-assessment-management-and-treatments. Accessed April 24, 2019.
- Yokell MA, Zaller ND, Green TC, Rich JD. Buprenorphine and buprenorphine/naloxone diversion, misuse, and illicit use: an international review. Curr Drug Abuse Rev. 2011;4(1):28–41.
- Cannabis, coca, and poppy: nature’s addictive plants [online]. Arlington, Va: Drug Enforcement Administration Museum, [n.d.]. Available at: www.deamuseum.org/ccp. Accessed July 27, 2017.
- Opiates/Opioids [online]. Farmington, Conn: National Alliance of Advocates for Buprenorphine Treatment, 2017. Available at: www.naabt.org/education/opiates_opioids.cfm. Accessed July 27, 2017.
- Roth-Deri I, Green-Sadan T, Yadid G. Beta-endorphin and drug-induced reward and reinforcement. Prog Neurobiol. 2008;86(1):1–21; doi: 10.1016/j.pneurobio.2008.06.003.
- Le Merrer J, Becker JA, Befort K, Kieffer BL. Reward processing by the opioid system in the brain. Physiol Rev. 2009;89(4):1379–1412; doi: 10.1152/physrev.00005.2009.
- Sprouse-Blum AS, Smith G, Sugai D, Parsa FD. Understanding endorphins and their importance in pain management. Hawaii Med J. 2010;69(3):70–71.
- Comer S, Cunningham C, Fishman MJ, et al. National Practice Guideline for the Use of Medications in the Treatment of Addiction Involving Opioid Use. Chevy Chase, Md: American Society of Addiction Medicine, 2015.
- Upadhyay J, Maleki N, Potter J, et al. Alterations in brain structure and functional connectivity in prescription opioid-dependent patients. Brain. 2010;133(pt 7):2098–2114; doi: 10.1093/brain/awq138.
- The Facts about Buprenorphine for Treatment of Opioid Addiction [online]. Rockville, Md: Substance Abuse and Mental Health Services Administration, 2015. Available at: https://store.samhsa.gov/product/the-facts-about-buprenorphine-for-treatment-of-opioid-addiction/sma15-4442. Accessed April 24, 2017.
- Federal Guidelines for Opioid Treatment Programs [online]. Rockville, Md: Substance Abuse and Mental Health Services Administration, 2015. Available at: https://store.samhsa.gov/product/federal-guidelines-for-opioid-treatment-programs/pep15-fedguideotp. Accessed April 24, 2019.
- Pharmacology of buprenorphine [online]. Farmington, Conn: National Alliance of Advocates for Buprenorphine Treatment, 2017. Available at: www.naabt.org/education/pharmacoloy_of_buprenorphine.cfm [sic]. Accessed April 24, 2019.
- Medication-assisted treatment improves outcomes for patients with opioid use disorder [fact sheet, online]. Philadelphia: Pew Charitable Trusts, 2016. Available at: www.pewtrusts.org/en/research-and-analysis/fact-sheets/2016/11/medication-assisted-treatment-improves-outcomes-for-patients-with-opioid-use-disorder. Accessed April 24, 2019.
- Welsh C, Valadez-Meltzer A. Buprenorphine: a (relatively) new treatment for opioid dependence. Psychiatry (Edgmont). 2005;2(12):29–39.
- Whelan PJ, Remski K. Buprenorphine versus methadone treatment: a review of evidence in both developed and developing worlds. J Neurosci Rural Pract. 2012;3(1):45–50; doi: 10.4103/0976-3147.91934.
- Buprenorphine: A Treatment for Opioid Addiction in the Privacy of a Doctor’s Office [brochure, online]. Farmington, Conn: National Alliance of Advocates for Buprenorphine Treatment, 2015. Available at: www.naabt.org/documents/naabt_brochure%20version%202.pdf. Accessed April 24, 2019.
- Dasgupta N, Bailey EJ, Cicero T, et al. Postmarketing surveillance of methadone and buprenorphine in the United States. Pain Med. 2010;11(7):1078–1091; doi: 10.1111/j.1526-4637.2010.00877.x.
- Winstock AR, Lea T, Sheridan J. Prevalence of diversion and injection of methadone and buprenorphine among clients receiving opioid treatment at community pharmacies in New South Wales, Australia. Int J Drug Policy. 2008;19(6):450–458; doi: 10.1016/j.drugpo.2007.03.002.
- Roux P, Villes V, Blanche J, et al. Buprenorphine in primary care: risk factors for treatment injection and implications for clinical management. Drug Alcohol Depend. 2008;97(1-2):105–113; doi: 10.1016/j.drugalcdep.2008.03.025.
- Alho H, Sinclair D, Vuori E, Holopainen A. Abuse liability of buprenorphine-naloxone tablets in untreated IV drug users. Drug Alcohol Depend. 2007;88(1):75–78; doi: 10.1016/j.drugalcdep.2006.09.012.
- Martin J. Adherence, diversion, and misuse of sublingual buprenorphine [guidance, online]. Providence, RI: Providers’ Clinical Support System for Medication Assisted Treatment, 2014. Available at: https://pcssnow.org/wp-content/uploads/2014/02/pcss-matguidanceadherence-diversion-bup.martin.pdf. Accessed April 24, 2019.
- Clinical Drug Testing in Primary Care. Technical assistance publication series, no. 32 [online]. Rockville, Md: Substance Abuse and Mental Health Services Administration, 2012. Available at: https://store.samhsa.gov/product/tap-32-clinical-drug-testing-primary-care/sma12-4668. Accessed April 24, 2019.
- Drug Testing: A White Paper of the American Society of Addiction Medicine. Chevy Chase, Md: American Society of Addiction Medicine, 2013. Available at: www.asam.org/docs/default-source/public-policy-statements/drug-testing-a-white-paper-by-asam.pdf. Accessed April 24, 2019.
- CDC guideline for prescribing opioids for chronic pain [summary, online]. Atlanta: Centers for Disease Control and Prevention, [n.d.]. Available at: www.cdc.gov/drugoverdose/pdf/guidelines_at-a-glance-a.pdf. Accessed April 24, 2019.
- Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain Management Patients. Langman LJ, Jannetto PJ, eds. American Association for Clinical Chemistry Academy Laboratory Medicine Practice Guidelines. Washington, DC: American Association for Clinical Chemistry, 2017. Available at: https://www.aacc.org/science-and-practice/practice-guidelines/using-clinical-laboratory-tests-to-monitor-drug-therapy-in-pain-management-patients. Accessed April 24, 2019.
- Beck O, Bosch T, Duncan C, et al. European Guidelines for Workplace Drug Testing in Urine. Spain: European Workplace Drug Testing Society, 2015. Available at: www.ewdts.org/data/uploads/documents/ewdts-urine-guideline-2015-11-01-v2.0.pdf. Accessed April 24, 2019.
- Belsey SL, Couchman L, Flanagan RJ. Buprenorphine detection in urine using liquid chromatography–high-resolution mass spectrometry: comparison with cloned enzyme donor immunoassay (ThermoFisher) and homogeneous enzyme immunoassay (Immunalysis). J Anal Toxicol. 2014;38(7):438–443; doi: 10.1093/jat/bku060.
- Berg JA, Schjøtt J, Fossan KO, Riedel B. Crossreactivity of the CEDIA buprenorphine assay in drugs-of-abuse screening: influence of dose and metabolites of opioids. Subst Abuse Rehabil. 2015;6:131–139; doi: 10.2147/sar.S88935.
- Elkader A, Sproule B. Buprenorphine: clinical pharmacokinetics in the treatment of opioid dependence. Clin Pharmacokinet. 2005;44(7):661–680; doi: 10.2165/00003088-200544070-00001.
- Melanson SE, Snyder ML, Jarolim P, Flood JG. A new highly specific buprenorphine immunoassay for monitoring buprenorphine compliance and abuse. J Anal Toxicol. 2012;36(3):201–206; doi: 10.1093/jat/bks003.
- Regina KJ, Kharasch ED. High-sensitivity analysis of buprenorphine, norbuprenorphine, buprenorphine glucuronide, and norbuprenorphine glucuronide in plasma and urine by liquid chromatography–mass spectrometry. J Chromatogr B Analyt Technol Biomed Life Sci. 2013;939:23–31; doi: 10.1016/j.jchromb.2013.09.004.
- Depriest A, Heltsley R, Black DL, et al. Urine drug testing of chronic pain patients. III. Normetabolites as biomarkers of synthetic opioid use. J Anal Toxicol. 2010;34(8):444–449.
- Petrides AK, Melanson SEF. LC–MS/MS testing for monitoring compliance in pain management [online]. Washington, DC: American Association for Clinical Chemistry, 2016. Available at: www.aacc.org/publications/cln/articles/2016/february/lc-ms-ms-testing-for-monitoring-compliance-in-pain-management. Accessed April 24, 2019.
- Syva Emit II Plus Buprenorphine Assay [package insert 10872256_A, online]. Tarrytown, NY: Siemens Healthcare Diagnostics, 2015. Available at: https://doclib.healthcare.siemens.com/doclibd?docdownload=doc_type_ifu%2f5863%2fdxdcm_09017fe9802949fe%2fbuprenorphine_assay_-_emit_ii_plus_-_rev_a_dxdcm_09017fe9802949fe-1538134434115.pdf&doclibid=1&doclibuserid=anouser&downloadrequestid=15562695753989&sdldt=arhjlp1cb0%2bvubj0zr6qmogj%2bdw%3d&zipdocs=. Accessed April 24, 2019.
- CEDIA Buprenorphine Assay [package insert 10007988-5-EN, online]. Fremont, Calif: Specialty Diagnostics Group, Thermo Fisher Scientific, 2016. Available at: https://fscimage.fishersci.com/images/D13661~.pdf. Accessed April 24, 2019.
- LZI Buprenorphine Enzyme Immunoassay for Beckman Coulter Synchron Systems [package insert, online]. Santa Clara, Calif: Lin-Zhi International Inc, 2016. Available at: https://lin-zhi.com/bci_applications/bcibup_pdf/pi/lzi.pi.beckmanbup.rev.15.062216.pdf. Accessed April 24, 2019.
- Buprenorphine Homogeneous Enzyme Immunoassay (HEIA) [factsheet, online]. Pomona, Calif: Immunalysis Corp, 2014. Available at: https://immunalysis.com/wp-content/uploads/2014/09/buprenorphine_heia_mkt-1012c_3.pdf. Accessed April 24, 2019.
- CEDIA Buprenorphine II Assay [package insert 10020852-1-EN, online]. Fremont, Calif: Specialty Diagnostics Group, Thermo Fisher Scientific, 2017. Available at: https://assets.thermofisher.com/tfs-assets/cdd/package-inserts/10020852-cedia-buprenorphine-ii-assay-en.pdf. Accessed April 24, 2019.
- Böttcher M, Beck O. Evaluation of buprenorphine CEDIA assay versus GC–MS and ELISA using urine samples from patients in substitution treatment. J Anal Toxicol. 2005;29(8):769–776.
- Pavlic M, Libiseller K, Grubwieser P, Rabl W. Crossreactivity of the CEDIA buprenorphine assay with opiates: an Austrian phenomenon? Int J Legal Med. 2005;119(6):378–381; doi: 10.1007/s00414-005-0544-x.
- CEDIA buprenorphine crossreactivity table for catalog nos. 100190 and 100240 (positive compounds) [online]. Fremont, Calif: Specialty Diagnostics Group, Thermo Fisher Scientific, 2011. Available at: https://static.thermoscientific.com/images/D15911~.pdf. Accessed April 24, 2019.
- Birch MA, Couchman L, Pietromartire S, et al. False-positive buprenorphine by CEDIA in patients prescribed amisulpride or sulpiride. J Anal Toxicol. 2013;37(4):233–236; doi: 10.1093/jat/bkt016.
- Manglik A, Kruse AC, Kobilka TS, et al. Crystal structure of the µ-opioid receptor bound to a morphinan antagonist. Nature. 2012;485(7398):321–326; doi: 10.1038/nature10954.
: Photo by Irinayeryomina courtesy Dreamstime (ID 118359239).