1. Urine screen interpretation basics
Michael E.M. Larson, Ph.D. Pain Management
Marshfield Clinic Minocqua Center

2. Continuing Medical Education (CME) Disclosure Urine screen interpretation basic. Michael Larson, PhD, June 14, I, Michael E M Larson, PhD, do have a relevant financial interest or other relationship with a commercial entity producing health-care related product and or services:
Affiliation/Financial Interest Name of Corporate Organization(s)
Grant/Research Support: Ameritox Ltd
Other Financial or Material Support Ameritox Ltd

3. Objectives Review basics elements of urine screens.
Discuss advanced methods of analyses using urine creatinine and statistical analyses.
Specific review of urine screen evaluation of marijuana.
Specific review of urine screen evaluation of buprenorphine.

4. Expertise Disclosure I am a psychologist, not a toxicologist!
Oversight of the Opioid Medication Management Team for MQA Pain Mgt for past 14 years.
Asked many questions:
Over 300 saved s from Drs. Grinstead and Flanagan (real toxicologists!), many more have been discarded.
Took many provider questions (well over a 4,000 by my count) that required me to think, review and learn.
Talked with other providers (Drs. Studt, Carpenter etc.) who had interest in urine.
Clinical Research Database (LAR30104):
Documented over 29,000 urine screens connected to medication list. Had to connect findings to a specific substance or medication.
Member – Team of providers and administrators that developed the Scheduled Medication Policy.

5. SAFETY TIP
Urine screens are one piece of data and should not be used in a vacuum!!!!
They are NOT perfect and we do not have a screen that can perfectly identify with complete certainty that the person is taking the medication as prescribed.
They are a TOOL to ADD TO clinical judgment, refill data, outside report, etc. to help make decisions.
They should NEVER and are NEVER the sole reason for a change in a person’s treatment plan.

6. Urine Testing 101 Why use urine screens? Why people don’t use them
They provide objective data of recent use
Unbelievably accurate. Hard to argue with the accuracy.
Depending on type of testing performed, learn:
Use of the prescribed medication.
Use of non-prescribed medications.
Use of illicit substances.
Why people don’t use them
Sometimes they are difficult to interpret
Difficult to ask people to submit a sample. Easier if you prompt them when signing the agreement.

7. Urine Test Basics (1) From Lab News Article per J. Flanagan PhD
Step 1: First step in a urine test is:
Screening based on antibody-antigen immunoassay.
This cross-reacts with structurally similar compounds.
If positive, really is called “presumptive positive”.
Can be a “false positive”. Only way to confirm that it is a “true positive” move to step two.
Can be also a “false negative” due to the THRESHOLD element.
Remember that a positive without confirmation can potentially impact pt care, BE CAREFUL. Also remember the false negative.

8. Urine Test Basics (2) From Lab News Article per J. Flanagan PhD
Step 2: confirmation and quantification:
This occurs by Gas Chromatography and Mass Spectrometry (GC/MS) which is very reliable.
My simplistic explanation of GC/MS:
Gas chromatography maps the various compounds.
Mass Spectrometry evaluates the mass (chemical structure) of the compounds.
Very specific and reliable.
Provides you with confirmation that the specific metabolite was present AND
Provides how much of the metabolites were present in the urine (quantification).

9. What is the purpose of urine testing?
Confirm patient is taking the prescribed opioid or Medication Assisted Treatment (MAT) such as buprenorphine;
Monitor abuse of other prescription medications (e.g., opioids, benzodiazepines and psychostimulants);
Confirm that they are avoiding any illicit substance use;
Confirm that they are not abusing ethanol in the context of opioid medication use.
If patient is only taking low dose or PRN medication may be negative (see negative drug screen results spreadsheet).

10. What type of urine screen should I order
What type of urine screen should I order? Use of Controlled Substances for Long Term Tx Plan Policy
URINE TEST TYPE: Pain Clinic Survey with Confirmation (PCS10) or a similar type of SURVEY that covers multiple substances.
Want to cover opioids (i.e., methadone, oxycodone, morphine, hydrocodone, hydromorphone, codeine) along with benzodiazepines, amphetamines (except methyphenidate), THCA, Cocaine, ethanol and BUPRENORPHINE
Add fentanyl or tramadol GC-MS if patient also on those medications
Can consider PCS-Mini (with / without conf) but this would NOT be appropriate for MAT patients.

11. Safety Tip regarding urine screens
Know what the type of screen you are order is going to show
Document in your note how the patient has been taking medications the previous hours for comparison
Don’t just focus on opioids, look at benzodiazepines and psychostimulants that may give you additional information on patient’s overall compliance
Check with the experts when it is not a clear and consistent result
Patients are EXPERTS with street knowledge of urine screen interpretation and sometimes professional knowledge.

12. Our method developed at the Minocqua Center
Use Urine Creatinine to adjust for sample hydration.
Urine creatinine (UC) is a by-product of muscle metabolism and excretes thru the urine at a relatively constant rate.
Allows for use to understand how hydrated (watery vs dense) the urine sample provided is.
If urine is watery, UC is low. If UC is high, then urine is more dense or has less water in it. Avg UC is around 100 mg/dL.
The level of metabolites or analytes in the urine will COVARY with the UC level.
If UC is LOW, then the amount of metabolites in the urine from the ingested drug will also be LOW.
If UC is HIGH, then the amount of metabolites in the urine from the ingested drug will also be HIGH.

13. Our research history
2009 Article (Larson & Richards, Clinical Medicine & Research) showed:
UC dramatically improved connection of drug dose to urine metabolite levels for individuals on methadone.
Use of UC allowed statistical analysis of urine screen thru the use of comparison to another group of individuals on the same medication and dose.
We were able to successfully identify individuals who were overusing, underusing and appropriately using methadone.
2015 Article (Larson, Berg & Flanagan, Journal of Opioid Management) showed:
UC also relevant for Morphine and Oxycodone products.
Drug dose and UC are highly statistically significant to drug metabolites level shown in the urine.

14. Additional background
US Patent on this method granted in August 2009 (US Patent No. 7,585,680 M. Larson and T. Richards). Patent covers the statistical comparison of an individual urine sample with the use of UC to correct for hydration to a normative database.
Patent has been exclusively licensed for use outside of Marshfield Clinic (MC) to Ameritox Ltd.
This means that I can only interpret urine screens using the statistical analyses when urine screen is ordered by a MC provider.
An understanding with Ameritox Ltd does allow me to statistically analyze urine screens if they use the Ameritox Ltd service outside of MC for GRANT PATIENTS ONLY. There is no payment associated with this understanding.
Royalties are paid to MC on a yearly basis at a constant rate and do NOT change regardless of any use factors. Please note that my royalties are NOT impacted by the above use or non-use with grant patients. There is NOT a conflict of interest given that there is NO CHANGE regardless of how many samples are interpreted or whether the method is used or not.

15. Example of PCS10
Urine Screen was "Clean and Appropriate" per Larson-Richards Protocol, findings: (*) Ratio Z-score of for OxyContin / oxycodone (male dose norms) is appropriate. (*) Negative for any illicit substances or other problematic medications.  
Urine Screen was reviewed per Larson-Richards Protocol, findings: (*) CONCERN: Ratio Z-score of for OxyContin / oxycodone (male dose norms) is LOWER than expected given that the pt had actually reported using a few more of the oxycodone than prescribed. This is UNUSUAL. (*) CONCERN: Positive for LOW LEVEL of THCA with ratio of This is likely passive inhalation but this has been an issue with this pt in the past.  

16. Cocaine Example
Urine Screen was reviewed per Larson-Richards Protocol, findings: (*) APPROPRIATE: Ratio Z-score of for oxycodone, on low end of expected range. (*) APPROPRIATE: Ratio Z-score of for temazepam. (*) PROBLEMATIC: Positive for THCA at a very low level with ratio of 0.20, which could represent passive inhalation. (*) PROBLEMATIC: Positive for COCAINE at very low level with ratio of 0.95. 

17. Interpretation guidelines for Marijuana Use of Urine Creatinine
Rules for Marijuana (THCA) interpretation:
Divide the THCA level by Urine Creatinine (example 100 / 50.0 = 2).
Identify that ratio and locate in table below.
If THCA / Urine Creatinine ratio is LESS THAN 0.5, this may be due to PASSIVE INHALATION (e.g., being in a closed space with other smoking marijuana and you are passively inhaling that smoke). This could also suggest a very infrequent user or a person who has not used for a several weeks and the THCA is excreting out of the system.
If THCA / Urine Creatinine ratio is 0.5 OR HIGHER, then we can accurately identify that the person has had ACTIVE INHALATION at some point in the recent past (e.g., 1-30 days or so).
CAUTION: Individuals with kidney dysfunction may show higher levels due to kidney problems, so if person has those known problems (e.g., recent low eGFR) the some caution may be indicated.
Low
High
Comment
0.0 to
0.49
Possible PASSIVE INHALATION or remote use or very low level use.
0.5 to
3.0
ACTIVE INHALATION CONFIRMED but likely fairly low level use (e.g., 1 x per week or less).
3.0 to
7.0
Active inhalation but likely more frequent. This may be in the several times a week user.
7.0 to
10.0
DAILY USERS will fall in this category. Likely chronic users.
10.0 or
Above
MULTIPLE TIMES PER DAY USERS. Likely CHRONIC AND CONSISTENT USERS.

18. Buprenorphine specifics.
Buprenorphine when ingested leads to two analytes that will be present in a urine screen:
Buprenorphine: This is the parent drug.
Norbuprenorphine: This is due to the body’s metabolism of the buprenorphine, this is an active metabolite in the body.
If the person is taking the medication in a STEADY STATE or consistently we will see:
Norbuprenorphine > (greater than) buprenorphine.
Usually the ratio will be 2 to 1 or more (e.g., norbuprenorphine will be 2 x higher than buprenorphine generally) but there is a fairly broad range.
This ratio allows analysis of the following:
Steady state use.
Loading Dose, where Buprenorphine is higher than Norbuprenorphine.
Weaning Dose, where Norbuprenorphine is significantly higher than Buprenorphine.
FILM DIPPING, where ONLY buprenorphine is present because the body has not shown any metabolism.

19. Buprenorphine specifics #2.
The combination of the two metabolites, when added together provide a great deal of stability and consistency with dose ingested
So – We can simply ADD the buprenorphine level in the urine to the norbuprenorphine in the urine together to get a TOTAL BUPRENORPHINE METABOLITES.
When we then CORRECT the Total Buprenorphine Metabolites with UC (simply divide the Total Buprenorphine Metabolites by UC) we get a TOTAL BUPRENORPHINE METABOLITES RATIO.
We then statistically COMPARE this ratio to other individuals (adjusted for liver / kidney function if present and gender, possibly age) to a Normative Dataset of people on the same dose that have been ASSESSED TO BE ADHERENT.
The results of this statistical comparison is what we call a Ratio Z-score, where roughly 66% should be between +/-1.00 and 95% should be between +/ We adjust our scale due to our inclusion of the actual sample in the distribution (which intentionally broadens our variability to be assured of adjustment for individual characteristics, such as fast or slow metabolizers).

20. Steady State User
Pt currently on buprenorphine or Suboxone therapy, urine screen was review per Larson-Richards Protocol, findings: (***) LEVEL ANALYSIS: Buprenorphine Total Metabolites Ratio Z-score of (female dose norms) is appropriate. (***) STEADY STATE ANALYSIS: NorB to Bup Ratio Z-score of suggests steady state use. (*) Remainder of urine screen was negative for problematic substances. This is considered a "CLEAN AND APPROPRIATE" urine screen.  

21. Buprenorphine example of Loading Dose and Overuse
Pt currently on buprenorphine or Suboxone therapy, urine screen was review per Larson-Richards Protocol, findings: (***) LEVEL ANALYSIS: Buprenorphine Total Metabolites Ratio Z-score of (female dose norms) is appropriate. (***) CONCERN - STEADY STATE ANALYSIS: NorB to Bup Ratio Z-score of suggests a PARTIAL LOADING DOSE. The NorB to Bup ratio is IN THE OPPOSITE DIRECTION and is a substantial concern. This is also VERY INCONSISTENT with her prior ratios on an INTRAINDIVIDUAL ANALYSIS. 
Pt currently on buprenorphine or Suboxone therapy, urine screen was review per Larson-Richards Protocol, findings: (***) CONCERN - LEVEL ANALYSIS: Buprenorphine Total Metabolites Ratio Z-score of 2.94 (female dose specific norms) is VERY ELEVATED strongly suggesting some level of OVERUSE. (***) STEADY STATE ANALYSIS: NorB to Bup Ratio Z-score of 0.99 suggests steady state use at a higher dose.
Pt's level was most consistent (estimate) with mg total use per day. She is prescribed 8 mg total per day. 

22. Buprenorphine example of FILM DIPPING
Pt currently on buprenorphine or Suboxone therapy. (*) Findings: (***) Buprenorphine: ratio of 219 (ratio Z-score for this dose 2.67, which is elevated). (***) Norbuprenorphine: NEGATIVE which is INCONSISTENT with steady state / consistent use. (***) This is most consistent with a LOADING DOSE (i.e., taking large amount of medication day or evening prior to urine screen. Given that the pt had about 18 hrs prior to submitting the urine screen, this provided him time to perform the loading dose. 
This pt now receiving Suboxone from another provider in Stevens Point with NO confirmatory testing performed.

23. Buprenorphine Weaning Dose
Pt currently on buprenorphine or Suboxone therapy, urine screen was review per Larson-Richards Protocol, findings: (***) LEVEL ANALYSIS: Buprenorphine Total Metabolites Ratio Z-score of (male norms) appears appropriate. (***) CONCERN - STEADY STATE ANALYSIS: NorB to Bup Ratio Z-score of 2.16 is in the correct direction but very high. This may suggest reduced use prior the urine screen or even running out prior to urine screen. 

24. REPEAT SAFETY TIP
Urine screens are one piece of data and should not be used in a vacuum!!!!
They are NOT perfect and we do not have a screen that can perfectly identify with complete certainty that the person is taking the medication as prescribed.
They are a TOOL to ADD TO clinical judgment, refill data, outside report, etc. to help make decisions.
They should NEVER and are NEVER the sole reason for a change in a person’s treatment plan.

25. Conclusions
Urine screens can be used to help us understand use patterns, especially with buprenorphine.
The use of Urine Creatinine and statistical analyses / comparisons can be helpful.
At times people do have unique metabolism and in those cases we can statistically analyze their new urine with their past urines to provide understanding of adherence.
The use of urine screens can provide information about aberrant use or tip us off to overuse, underuse, loading doses, weaning doses or dipping a film.
If you have questions, please contact me.

26. larson. michael@marshfieldclinic
Michael Larson PhD Marshfield Clinic – Minocqua Center Please contact with any specific questions or for any of the handouts.