Laboratory Challenges in Clinical Toxicology of Pain Management

By Michael (Rusty) Nicar &

Marc McCain

Clinical Tandem Mass Spectrometry:Cutting Edge Technology for the Clinical Lab

Children’s Medical Center October 2010

Texas Medical Board Rules 2010

What is Chronic Pain: “a state in which pain persists beyond the natural course of an acute disease or healing of an injury.”

Appropriate drug therapy: “recognized by consensus.”

“A physician may require laboratory tests fordrug levels upon request.”

How Many Patients Have Chronic Pain?

1 out of 4 Americans have recurrent pain

1 out of 10 have pain of at least 1 yr duration

Treatment of Choice for Chronic Pain

CHRONIC OPIOID Rx

Hydrocodone is the most prescribed drug in the USA. Others used for pain:morphine, codeine, fentanyl, oxycodone, hydromorphone, oxymorphone, meperidine, methadone.

Why Do Pain Doctors Drug Test

Concerns: Drug Diversion

(majority of overdose deaths in W. Virginia were due todiversion of opioids, JAMA 2008 300:2613)

Taking non-prescribed or illegal drugs

Taking more than the prescribed dose

Overdose

Estimated Number of Emergency Department Visits in 2006:

Opioids – 250,000Acetaminophen – 50,000NSAIDS – 35,000

What Medications Do Pain Patients Take

What Are Patients Taking

CT: Cymbalta, Lyrica, Fentanyl, Hydrocodone

GG: Flexeril, Rozerem, Lortab, Allegra, Relafen

TK: Duragesic, Percocet, Ambien

RT: Lyrica, Norco

LV: Zantac, Carisoprodol, Wellbutrin, Topamax, Ambien,Hydrocodone, Celebrex, Flomax, Lexapro, Morphine,Baclofen

What Are Patients Taking

RR: Oxycontin, Percocet, Topamax, Metformin, Foltix, Lasix, Singulair, HCTZ, Nifedapine, Diovan, Premarin, Zetia, Omega 3

ML: Sirolimus, Cellcept, Metoprolol, Methadone,Effexor, Synthroid, Norvasc, Lisinopril,Allegra, ASA

OP: Skelaxin, Robaxin, Norco, Methadone

FH: Fentanyl, Tramadol

Why Do Pain Doctors Drug Test

State regulators require physicians to test patients during pain management.

Testing improves the Quality of Care.

Testing is the Standard Of Care for pain management.

Pain Physician 11:S5-S62, 2008.Journal of Pain 10:113-130, 2009.

Laboratory Monitoring

“Standard of Practice” for laboratory monitoring of pain patients is urine drug testing.

Because it was readily available, rapid, non-invasive, and inexpensive.

Not because it is the best scientifically.

Urine Drug Positives

Study from Johns Hopkins in 11,000 chronic pain patients confirmed positives in theiurine specimens (JAT 2008):

Amphetamines 2% Barbiturates 3% Benzodiazapines 22%

Cannabis 9% Carisoprodol 3% Cocaine 3%

Fentanyl 4% Meperidine 1% Methadone 11%

Opiates 82% Propoxyphene 4%

Drug Screen Results in Dallas

At CHOICE Laboratory, I see the following distribution on AU urine drug screens:

Negative – 25%Opiate – 50%

Opiate + Oxycodone – 16%

Illicit Drug Use Among Pain Patients

Patients must also be tested for illicit drug use.

A study in Kentucky reported the followingpercentage of pain patients using:

Marijuana – 11% (13% of females, 7% of males)Cocaine – 5%Methamphetamine – 2%

Pain Physician 9:215-226, 2006

Illicit Drug Use in Dallas Patients

At Choice Labs:

Marijuana (THC positives confirmed) – 8% *

Cocaine – 2% *

Methamphetamine – 1%

*no false positives by AU immunoassay screen

Limitations of Immunoassays

Crossreactivity of the antibody

Can’t identify specific drugsOpiate = morphine + codeine + hydrocodone

Cut-offs (Qualitative)Commercial assays come with cut-offs

Limitations of Immunoassays

False Positives due to crossreactivity:

Cannabinoids – Protonix, Daypro

Methadone – diphenhydramine, propoxyphene

PCP – meperidine, dextromethorphan

Oxycodone - Oxymorphone

Instrumentation

Immunoassays for single drugs can be quantitative and the Beckman Olympus AU has a semi-quantitative mode for drug classes (ie Opiates, Benzos) – but these assay still use antibodies and have limitations.

Confirmation instrument of choice for pain management labs:

LC-MS/MS

Why LC-MS/MS

SPECIMEN PREPARATION:

LC-MS/MS requires significantly less specimen prep than GC/MS

GC/MS – treatment and derivatization

LC-MS/MS – little or no treatment andno derivatization“Dilute & Shoot”

Why LC-MS/MS

SPECIMEN VOLUME:

LC-MS/MS requires significantly less specimen than GC/MS

GC/MS – 2-5 mLs

LC-MS/MS – 0.2-1 mL

Why LC-MS/MS

SENSITIVITY

LC-MS/MS requires dilution of specimens while GC/MS requires specimen concentration

GC/MS Opiate LOD = 100 ng/mL

LC-MS/MS Opiate LOD = 25 ng/mL

Why LC-MS/MS

Single scan determination of many drugs in minutes.

But…..CPT codes are for “assays” andMedicare pays for each assay – not for each drug measured.

The Pain Drug Screen

Amphetamine Barbiturates Benzodiazepines

Cannabinoids Cocaine MDMA

Methadone Opiates PCP

Propoxyphene Oxycodone TCAs

Creatinine Alcohol Cotinine

Buprenorphine Adulterants

The Pain Drug Confirmations

Amphetamine, Methamphetamine, MDA, MDMA, MDEA

Buprenorphine, Norbuprenorphine

7-aminoclonazepam, Hydroxyalprazolam, Oxazepam, Lorazepam, Nordiazepam, Tamazepam

Carisoprodol, Meprobamate

Benzoylecgonine

Methadone, EDDP

Propoxyphene, Norpropoxyphene

The Pain Drug Confirmations, cont

Morphine, Codeine, Hydrocodone, Hydromorphone Oxycodone, Oxymorphone, 6-MAM

Amitriptyline, Nortriptyline, Imipramine, Desipramine, Doxepin, Desmethyldoxepin, Cyclobenzaprine,

Clomipramine, Norclomipramine

Fentanyl

Tramadol, Meperidine, Normeperidine

Amobarbital, Butabarbital, Pentobarbital, Phenobarbital, Butalbital, Secobarbital

THC-COOH

Children’s Medical Center 2010

Thank You.