Opiates Agreements and Drug testing in Pain Management Lokesh Ningegowda, MD Department of Pain Management Anesthesiology Institute Cleveland Clinic OBJECTIVES Define : Tolerance, dependence, addiction, abuse, misuse Identify low, medium and high risk patients Need for opioid agreement and do urine drug screening Constituents of opioid agreement Types of drug screening techniques available Interpreting the result of urine drug testing Types of opioids and their metabolites Limitations of Urine drug testing (false positive and False negative results)
INTRODUCTION Opioids are extensively used in treating chronic pain despite limited evidence of its effectiveness. Controversial for managing chronic Nonmalignant pain (CNMP)? Efficacy Abuse potential (addiction and diversion) Clinician responsibility Treat patients Decrease abuse THE PROBLEM Opioid abuse in patients with chronic pain 18-41% Illicit Drug use in patients in chronic pain management setting is 14-34% Prescription drug diversion. Increased health care costs in patients with nonadherence to opoiod therapy.
What Constitutes substance Abuse? Willful misuse of opioids/ other drugs which may include drug diversion Maladaptive pattern of substance use leading to: Significant impairment Using inappropriate substances Involved in recurrent substance related legal problems Continuing use in the face of adverse consequences ADDICTION TOLERANCE DEPENDENCE Addiction, Tolerance and Dependence
ADDICTION Addiction is a primary, chronic, neurobiologic disease, with genetic, psychosocial, and environmental factors influencing its development and manifestations. It is characterized by behaviors that include one or more of the following: Impaired control over drug use compulsive use continued use despite harm craving Addiction = Compulsive use of a medication despite dysfunction and harm Biological factors : < 45 yrs gender Fhx hx of prescription drug abuse Cigarette smoking Psychiatric factors: preadolescent sexual abuse bipolar disorder, depression Social factors: prior legal problems, hx of MVA, poor family support
Differentiate between addiction and pseudoaddiction Pseudoaddiction: Will stop dose escalation or reduce dose once pain controlled Will not try to achieve euphoric effects. No signs of intoxication (Sedation, confusion) Focus on side effects and consequences of side effects Follows recommendations for other forms of treatments. DEPENDENCE Physical dependence is a state of adaptation that is manifested by a drug class specific withdrawal syndrome that can be produced by: abrupt cessation, rapid dose reduction decreasing blood level of the drug administration of an antagonist.
TOLERANCE Need for increased dosage of a drug to produce the same level of analgesia that previously existed. It is a state of adaptation in which exposure to a drug results in a diminution of one of more of the drug s effects over time. Progressively higher doses required to maintain same degree of pain control Uncommon Does not imply addiction Tolerance Mechanism unknown Up- regulation of opioid receptors Decreased concentration of endogenous opioids Inhibition of cyclic AMP synthesis Reduced sensitivity of opioid receptors
ADDICTION TOLERANCE DEPENDENCE Diversion and Misuse/ Abuse What is the controversy? Under treatment of pain vs Drug abuse and addiction in the US Limited tools for treating pain vs Lack of objective data on efficacy of long-term therapy Physicians as caregivers vs Law enforcement agents Medical malpractice vs Criminal activity
Drug Abuse Prevalent in USA Alcohol Marijuana Prescription Pharmacy and distributor theft Diversion Cocaine, methamphetamine Estimated 7-12% US and 20-36% chronic pain Prescription Abuse
ED visits Screening tools to monitor opioid adherence Identify patients needing chronic opioid therapy Establish realistic expectations and guidelines CAGE and CAGE- AID Opioid risk tools (ORT) The Screener and Opioid Assessment for Patients with Pain (SOAPP/ SOAPP-R ) Drug abuse screening test (DAST) Pain Medication questionnaire (PMQ) Screening tools for addiction risk (STAR) Etc, No single tool can be uniformly accepted and broadly applied. 5 factors predicting abuse: h/o substance abuse, legal problems, heavy smoking, mood swings.
Red Flags for abuse Lost/stolen prescriptions Early refills Calling unfamiliar physicians Use for psychoactive effect - Suggested by rapid escalation - It is likely that desired psychoactive effect requires intoxication - Develops tolerance to this in contrast to analgesia Red flags for abuse Demands end-of-office-hour appointments or arrives just after close (running late) Needs immediate action Refuses physical examination or tests Prohibits release of medical records Cannot or will not provide past providers Uses excuses of visiting from out of town and lost or stolen prescriptions No medical basis for allergies to nonopioids Unusual knowledge of controlled substances History of previous substance abuse by the patient and/or family are strong indicators of the likelihood of continued abuse.
Patients risk profile LOW risk: Chronic non cancer pain No hx of substance abuse No major psycho/ social issues. MEDIUM risk Prior hx of substance abuse or dependence Family hx of substance abuse Psychiatric issue (depression, bipolar) HIGH risk Active addictive disorder (determined by hx or UDS) Should likely be managed by a pain specialist Risk Profile Management strategies Low risk : primary care, watchful for development of aberrant drug behaviors increase risk category Moderate risk : more frequent visits, limit opioid quantities, treat comorbid depression, sleep disturbance. Involve psychologist, mindfullness training, biofeedback High Risk: all the above, strict contracts with plan for discontinuation of opioid Rx, pill/patch counts, frequent UDT, use of extended release medications and a thought out referral network (detox specialist, psychiatrist etc)
Treatment Plan and expectations Discuss Treatment Plan, goals and expectations Discuss Opioid side effects and risks Informed consent and opioid agreement Discuss about periodic UDT, OARS, pill count etc. Define exit strategy in case of abbrent drug behaviour Consequences of non compliance ADDICTION TOLERANCE DEPENDENCE Opioid Informed Consent and Agreement
Opioid Informed Consent and Agreement Opioid informed consent: Discuss Risk, benefits, alternatives of chronic opioid therapy and sign the consent. Discuss in detail about the side effects. Opioid agreement Should include : One prescribing physician One designated pharmacy Not to sell or share medications Not to abuse illicit drugs like cocaine Urine/ serum drug screening when requested No early refills or early medication call in. Lost or stolen medications would generally not replaced and may need to be reported to the police before giving additional prescription. Reasons for which opioid therapy may be discontinued eg: violation of agreement. Etc,. Schedule 2 Rx for maximum of 3 months Sec. 1306.12 Refilling Prescriptions; Issuance of Multiple Prescriptions (a) The refilling of a prescription for a controlled substance listed in Schedule II is prohibited. (b)(1) An individual practitioner may issue multiple prescriptions authorizing the patient to receive a total of up to a 90 day supply of a Schedule II controlled substance provided the following conditions are met: (i) The individual practitioner properly determines there is a legitimate medical purpose for the patient to be prescribed that controlled substance and the individual practitioner is acting in the usual course of professional practice; (ii) The individual practitioner writes instructions on each prescription (other than the first prescription, if the prescribing practitioner intends for that prescription to be filled immediately) indicating the earliest date on which a pharmacy may fill the prescription; (iii) The individual practitioner concludes that providing the patient with multiple prescriptions in this manner does not create an undue risk of diversion or abuse; (iv) The issuance of multiple prescriptions as described in this section is permissible under the applicable state laws; and (v) The individual practitioner complies fully with all other applicable requirements under the act and these regulations as well as any additional requirements under state law. (2) Nothing in this paragraph (b) shall be construed as mandating or encouraging individual practitioners to issue multiple prescriptions or to see their patients only once every 90 days when prescribing Schedule II controlled substances. Rather, individual practitioners must determine on their own, based on sound medical judgment, and in accordance with established medical standards, whether it is appropriate to issue multiple prescriptions and how often to see their patients when doing so. 32 This new rule would permit an individual practitioner to issue multiple prescriptions authorizing the patient to receive a total of up to a 90 day supply of a Schedule II controlled substance. Due to the fact that the public comment period of 60 days has now concluded, the DEA is responsible for determining whether this proposed regulation becomes law.
Pain Management Department OPIOID MAINTENANCE AGREEMENT The long-term use of Opioid medications (narcotic analgesics) is somewhat controversial because of the uncertainty regarding the extent to which this treatment actually improves the patient s quality of life. There is the potential risk for addiction. The extent of this risk is not certain. Because these drugs all have potential for abuse or diversion, rather strict accountability is necessary when these medications are prescribed. The goal of treatment is to reduce pain to a tolerable level that allows increased function. Daily use of narcotics is associated with certain risks; the risks include but are not limited to: Addiction. Withdrawal symptoms. Allergic reactions, overdose and/or fatal complications. Breathing problems. Drowsiness, dizziness and/or confusion. Impaired judgment and inability to operate machines or drive motor vehicles. Nausea, vomiting and /or constipation. Development of tolerance. Pain Management Department OPIOID MAINTENANCE AGREEMENT I agree to the following guidelines: I will take this medication only as prescribed and I will not change the amount or dosing frequency without authorization from my physician. Unauthorized changes may result in my running out of medications early, and early refills will not be allowed. I will obtain all narcotics from one physician or, during his or her absence, by the covering physician. Requests for pain medications from the on-call physician (nights and weekends) will not be honored. I will obtain all narcotics from one pharmacy. I must notify the Pain Management Department if I change pharmacies. The pharmacy that I have selected is: ; phone number is:. The prescribing physician has complete liberty to discuss fully all diagnostic and treatment details with the pharmacists at the dispensing pharmacy for purposes of maintaining accountability. I will submit to random pill counts, urine and/or serum toxicology screens as requested to monitor my compliance. Presence of unauthorized substances may prompt referral for assessment of addiction and discontinuation of further Opioid prescriptions. I will not share, sell or otherwise permit others to have access to these medications. Medications will not be replaced if they are lost or stolen. It is expected that I will obtain a safe for my medications and guard against theft. I understand that prescriptions may be issued early, for example, if the treating physician is going to be out of town, or if I am going to be out of town when a refill is due. However, I also understand and accept that these prescriptions will contain instructions to the pharmacist that they not be filled prior to the appropriate date. If legal authorities have questions concerning my treatment (as might occur, for example, if there was a concern that I was obtaining medications at several pharmacies), I hereby waive all confidentiality, including my patient-physician privilege and I consent to giving the authorities full access to my Records of narcotic administration. I UNDERSTAND AND AGREE THAT FAILURE TO ADHERE TO THESE POLICIES WILL RESULT IN PERMANENT CESSATION OF NARCOTIC PRESCRIBING BY THIS PHYSICIAN AND MAY RESULT IN MY DISMISSAL FROM THE ENTIRE CLEVELAND CLINIC PAIN MANAGEMENT DEPARTMENT, SYSTEMWIDE. Patient Signature*** Date Physician Signature Date ***Patients receiving methadone for pain management additionally agree to not consume alcohol and further agree to not add or discontinue ANY medications, including over the counter drugs without contacting the pain center. / / (patient initials and date)
Do and Don t Do: Recognize that some of your patients may be targets or may be targeting you. Obtain additional consultation if you suspect addiction or abuse Consider predominantly sustained release preparations Obtain frequent urine toxicology Don t: Ignore red flags Ignore your own policies and procedures Disregard information from family and friends of potential abuse Continue to prescribe if you have knowledge of abuse (non-medical use) or diversion Continue to prescribe if treatment goals are not being met Document Four A s on every visit Analgesia Adverse events ADL s Aberrant drug related behaviors and physical examination
Prescription drug abuse scams I was robbed I am allergic to My house burned down The only thing that has worked for me You are the first doctor I can trust and understands The dog ate.. Termination of Opioid Agreement Unauthorized dose escalation Doctor shopping Dangerous medication combinations Use of recreational / illicit drugs UDT negative for prescribed drugs UDT positive for non prescribed drugs
If patient has breached opioid agreement Detox consult / substance abuse therapy Chronic pain rehabilitation program No further opioid or schedule 2 drugs and wean off narcotics but you cannot abandon patient If you feel patient has agenda of misleading you and patient does not indicate by actions and words that he will follow a plan then consider a discharge letter with a list of other providers in the area. If patient was negative for prescribed drug he will not need to be tapered off his medications ADDICTION TOLERANCE DEPENDENCE Urine Drug Screening
UDT UDT is a part of Prescription Monitoring in patient on chronic opioids for CNMP Other methods include: Patient self report Behavioral monitoring OARS Pill count Drug testing ( urine, blood, saliva, hair, sweat) Urine Drug Testing- Why?? Reasons to do UDT: Effectively monitor patient compliance of therapy (presence of prescribed opioid) Detect abuse or diversion Detect use of non prescribed drugs Presence of illicit drugs
10 P s: Protecting Patient Protecting practitioner???? Protecting the pain therapy plan Protecting the community Protecting society Promoting cost effectiveness Protecting resources Practicing safe and effective medicine Practicing and fulfilling ethics in medical practice Preserving access to therapy Advantages of urine testing over other specimens Best biologic specimen for detecting presence or absence of certain drugs Ease of administration. Cost effective Metabolites excreted for longer period.
Limitations of UDT (Screening methods) Cutoff threshold- may give rise to false negative results if below threshold level Cross reactivity can give rise to false positive results Pharmcokinetics, pharmocodynamics and pharmacogenetics- variation. Lab technology Chance of adultration Who should be tested? Careful Patient selection in high risk patients Vs Universal precaution approach UDT Should be standard practice for all patients treated with chronic opioids This will reduce the risk of substance abuse Protect physicians from accusations of discrimination Prevent monitored patients from feeling stigmatized as having exceptional risk profile
Collecting urine specimen Obtain samples before meeting (So patient does not leave without providing sample) Ensure samples are free of contaminants and carefully labeled Minimize the likelihood of fraudulent sample Federally mandated testing (DOT) requires water shutoff, colored toilet water, chain of custody, split sample, secure storage of non- negative samples Detecting adulterated urine - Specimen Validity test Inspection: color, foaming characteristic (normally yellow color with foam and urine of same color) Temperature within 4 mins of collection ( 90-100 deg F) many collection cups contain temp strip. Urine ph ( 4.5 to 8) Creatinine level (Normal >20mg/dl) Tests to detect various adulterants If urine does not meet these parameters retest Witnessed collection specimen If urine sample continues to be outside of norm consider as refusal to test
Adulteration or subversion of urine drug testing Use of diuretics Substitution of specimen Urinator - freeze dried clean urine. Quick reconstitution and warmed to body temperature. Available on internet. Urine luck Urinaid - contains gulteraldehyde which interferes with IA. Niacin- prevents detection of THC Available online
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Screening test Advantages: Rapid testing Can be tested as POC in the clinic Minimal training is required for staff to do this Inexpensive Can handle high volume Disadvantages: Qualitative (Non quantitative) cut off values to detect Less sensitive to semisynthetic/ synthetic opioids (eg, oxycodone) Subject to cross reactivity Cannot determine exposure time, dose, frequency of use Confirmatory test- Laboratory test Advantages: Quantitative Highly specific and sensitive More accurate than POC testing Will detect very low levels Disadvantages: Relative expensive Need laboratory services Takes longer time
Which POC testing should be sent to the lab? Why don t we just do confirmation lab tests for everyone? Confirmation should be done for: All samples testing negative for prescribed opioids Samples positive for non prescribed opioids Sample positive for illicit drugs Range 20-60% Cost between immunoassay (25$) to GC/ MS/ LC ( 500-1000$) is high Routine excessive UDT with confirmation can result in annual charges of > 10,000 $. (Eg: If all the patients on chronic opioids gets monthly refills and when they come for refills, UDT with confirmation is mandatory!!!!!- is it cost effective????) Appropriate use of immunoassay with confirmation of abnormal result will be cost effective with provision of appropriate care. Drug Cross Reactants (false Positive) DRUG Cannabinoids: Opioids: Amphetamines: PCP: Cross reactant (false+) NSAIDS, Marinol, Protonix Poppy seeds, rifampin, chloropromazine, dextromethorphan, quinine ephedrine, pseudoephedrine, trazodone, bupropion, desipramine,amantadine, ranitidine, vicks vapor spray, methylphenidate Chlorpromazine, thioridazine, meperidine, dextromethorphan, diphenhydramine, doxylamine Benzodiazepines: Oxaprozyn (Daypro), some herbal agents ETOH: Methadone: asthma inhalers (sometimes) propoxyphene, seroquel
UDT Drugs tested Opioids including oxycodone and methadone Benzodiazepines Barbiturates Marijuana Cocaine Amphetamines Methamphetamines Also: ETOH, Fentanyl This depends on the type of kit being used. Some kits may not be testing for specific opioids and may by generic for opiates in which case there is a chance for high incidence of false negative for synthetic and semi synthetic opioids. Drug Detection time in urine
Metabolites of Opioids Morphine: M3G, M6G,Normorphine, hydromorphone (minor) Oxymorphone: oxymorphone 3 glucuronide, oxymorphol Hydromorphone: Hydromorphone 3 gucuronide, dihydromorphine Oxycodone: Noroxycodone, oxymorphone, oxycodols Codeine: Norcodeine, Morphine, Hydrocodone (minor) Hydrocodone: Normorphine, Norhydrocodone, Hydrocodol, Hydromorphone, Hydromorphol Propoxyphene: Norpropoxyphene Heroin: Morphine, 6 monoacetyl morphine Types of opioids Natural: Morphine, Codeine Semi synthetic: Heroin, hydromorphone (dilaudid), hydrocodone (vicodin), oxycodone (percocet), oxymorphone (opana), buprenorphine (suboxone) Synthetic: Fentanyl, meperidine, tramadol, methadone, dextropropoxyphene
Differentiating which opioid was taken Presence of synthetic/ semi synthetic opioids like oxycodone, fentanyl, tramadol, methadone and buprenorphine if not prescribed means that they were ingested and indicates abuse. (Because no other opioid produces these as metabolites) Presence of morphine, oxymorphone, hydrocodone, hydromorphone can be due to metabolites of other opioids and presence of these metabolites even though not prescribed may not indicate abuse if the prescribed opioid is known to produce one of them as metabolites. Morphine, Codeine or Heroin Codeine: metabolized to Morphine and Hydrocodone (minor) (Small amount of Hydromorphone) Heroin: metabolized to Morphine and 6-MAM (Monoacetyl morphine) If patient is prescribed codeine and UDT is positive for Morphine and codeine, quantitative test (GC/ MS) is done to know the level of morphine. If morphine level is higher then codeine, it may indicate patient may be taking morphine or heroin separately T ½ of heroin is 3-5 mins, t ½ of 6MAM is 25-30 mins so the utility of detecting these is limited for few hours.
Oxycodone and Oxymorphone Oxycodone is metabolized to noroxycodone and oxymorphone If UDT of patient prescribed oxycodone is positive for oxymorphone, quantitative analysis needs to be done to confirm that relative quantity of oxycodone is > oxymorphone (except at ate stage of excretion) If patient is prescribed oxymorphone, it is easy to interpret the UDT of that patient since it does not produce any metabolites which can be mistaken for prescribed opioids. Hydrocodone Most commonly prescribed opioid analgesic Metabolised to dihydrocodeine and hydromorphone. Codeine may produce hydrocodone as a minor metabolite Codeine Hydrocodone Hydromorphone But the amount of hydrocodone produced is very low to levels of hydromorphone. So, if patient is on codeine and UDT is positive for hydromorphone, it indicates hydromorphone was taken seperately If patient on hydrocodone has codeine in UDT, it indicates that codeine was taken separately since hydrocodone does not produce codeine as a metabolite.
Synthetic/ Semi synthetic opioids Presence of the following in UDT indicates that they were taken Oxycodone Fentanyl Methadone Tramadol Buprenorphine Propoxyphene If a patient is tested positive for one of the above and it is not being prescribed it indicates abuse Non opioid drugs of abuse Benzodiazepines: False positive POC (IA) NSAID s fenoprofen, flubiprofen, indomethacin, tolmetin, zoloft (Confirmation by GC/ MS) Cocaine: POC (IA) is sensitive for cocaine and its metabolites benzoylcgonine and ecgonine methylester. Little cross reactivity. Amphetamine / Methamphetamine: Cross reactivity to OTC meds like ephedrine/pseudoephedrine, trazodone, selegeline, bupropion. Confirmation by GC/MS. Marijuana: -THC. Passive exposure to marijuana does not produce positive urine test. False positive with antiviral efavirenz (antiretroviral) or PPI pantaprazole. Presence needs confirmatory test by GC/MS.
Algorithm for urine drug testing Baseline UDT: helps in establishing the reliability of patients reported substance abuse. Universal approach- all patients are treated in similar fashion Monitoring for compliance: Baseline monitoring Compliance monitoring within 1-3 months routine random monitoring every 6-12 months Patients with abnormal results or high risk patients may need more frequent monitoring No evidence to suggest who should have UDT and how often UDT needs to be done Interpretation of results UDT should not be considered as definitive and decision should not be based on UDT alone. UDT should be considered in tandem with other forms of patient monitoring such as regular follow up, behavioral observation, risk assessment, reviewing prior history of drug abuse or substance abuse.
UDT results 5 scenarios 1. Positive for prescribed drug and negative for other drug or illicit drug 2. Negative for prescribed drug: Possible noncompliance, diversion, false negative results. Needs confirmatory test with GC/ MS. Test may be repeated. 3. Urine drug positive for nonprescribed opioid or benzodiazepine: False positive, metabolites of other prescribed opioid, multisourcing. Confirmation by GC/ MS, get OARS report (prescription drug record) 4. UDT positive for illicit drug: Confirmation and appropriate action 5. Sample tampering: Repeat UDT supervised/ witnessed collection 10 steps of Universal Precautions in Pain Medicine 1) Make a diagnosis with appropriate differential 2) Psychological assessment including addictive disorders 3) Informed consent 4) Treatment / opioid agreement 5) Pre and post intervention assessment of pain level and function 6) Appropriate trial of opioid therapy with or without adjunctive medication 7) Reassessment of pain score and level of function 8) Regularly assess the 4 A s of pain medicine 9) Periodically review pain diagnosis and co morbid conditions including addictive disorders 10) Documentation
ADDICTION TOLERANCE DEPENDENCE Oral fluid drug testing Company claimed benefits Administered anywhere in 2-5 mins Accuracy of blood No adulteration or excuses Always observed / witnessed collection Detects drugs and metabolites Detects recent usage and trace quantities. Low cut off levels
Suggested readings: 1) Urine drug testing in chronic pain Pain physician 2011;14:123-143- Review 2) Urine toxicology testing in chronic pain management Postgrad Med. 2009 Jul;121(4):91-102. Review. 3) Role of urine drug testing for patients on opioid therapy Pain Pract. 2010 Nov-Dec;10(6):497-50 4) Monitoring opioid adherence in chronic pain patients: Assessment of riesk of substance misuse Pain Physician 2011; 14:E119-E131 PILLS KILL - PAIN DOES NOT Thank you ningegl@ccf.org