Hot Topics in Chronic Pain Management: Questions Every Pain Pharmacist is Asked

William D. Gersch PharmD, BCPSClinical Pharmacy Specialist – Pain Management

Kaiser Permanente Colorado

Colorado Pharmacists Society2016 Winter CE and Ski Seminar

January 9th - 13th

I have no conflicts of interest to disclose.

Conflict of Interest Disclosure

Objectives

Summarize the role of buprenorphine for chronic pain management

Critique the rationale for opioid dose limiting

Develop criteria for naloxone prescribing/dispensing

Describe an appropriate UDS monitoring program in clinical practice

BUPRENORPHINE AND CHRONIC PAIN

Buprenorphine is indicated for the management of chronic pain?

Green – True

Pink – False

Background

Semisynthetic derivative of thebaine, an opioid alkaloid Mixed partial agonist opioid receptor

– Mu receptor partial agonist– Kappa receptor antagonist

C-III medication for the management of opioid dependence and chronic pain– Suboxone® (buprenorphine/naloxone) and Subutex® (buprenorphine) are FDA

indicated for opioid dependence– Butrans® (buprenorphine) is FDA indicated for the management of chronic

pain

Heit HA et al. Clin J Pain. 2008; 24:93-97

Advantages

Long-acting due to slow dissociation from the opioid receptor Ceiling effect for CNS and respiratory depression

– Higher doses result in antagonistic effect

Potentially less hyperalgesia due to partial agonist properties No dose adjustments for renal impairment Less constipation Not associated with hypogonadism due to lack of HPA axis impact Potentially less immunosuppression

Boas RA et al. Br J Anaesth 1985; 57:192–196Sporer KA. Ann Emerg Med 2004; 43:580–584Raisch DW et al. Ann Pharmacother 2002; 36:312–321.Pergolizzi JV et al. Acta Anaesthesiol Taiwan 2015; 53(2):71-6Sacerdote P. Curr Opin Support Palliat Care 2008; 2:4-18

High Receptor Affinity – Blessing or Curse

Lower level of physical dependence Potentially more mild withdrawal symptoms Improves safety profile if non-prescribed opioids are taken Challenge for incident pain management Resistance to opioid antagonist such as naloxone in overdose

situations

Breen CL et al. Drug Alcohol Depend 2003; 71:49–55.

Disadvantages

Analgesic effects may not be as powerful as a full opioid agonist Drug interactions – CYP 3A4 inducers

– Increases nor-buprenorphine which has more potent respiratory effects– QTc prolonging agents

Abuse– Finland

56% of opioid agonist treatment were due to buprenorphine 33% of clients reported buprenorphine as their primary drug of abuse

– French survey noted that 54% treatment patients used non-prescribed buprenorphine– Polysubstance abuse with other CNS depressants is common to achieve sedation,

intoxication and euphoria

UDS monitoring is more challenging/expensiveOhtani M et al. J Pharmacol Exp Ther 1995; 272:505–510EMCDDA. 2008 National Report (2007 Data) to the EMCDDA by the Finnish National Focal Point, STAKES. Available at: http://www.emcdda.europa.eu/attachements.cfm/att_86775_EN_NR_2008_FI.pdf. Accessed November 16, 2015.EMCDDA. Buprenorphine—Treatment, Misuse and Prescription Practices. Lisbon: EMCDDA; 2005. Accessed November 16, 2015.

Prescribing Pearls

Use of buprenorphine “off-label” for the management of pain is not prohibited under DEA regulations– Prescribers do not need a waiver from Center for Substance Abuse Treatment

(CSAT)– Prescribers should not place an “X” before their DEA number

Ideally if used for chronic pain, prescribers should note one or both of the following on the prescription to avoid confusion: – “Chronic Pain Patient”– “Off-labeled Use”

Heit HA et al. Pain Med 2004; 5:303–308

Conversions

Suboxone® and Subutex® sublingual tablets– 0.4mg SL buprenorphine = 30mg PO morphine– Maximum dose for chronic pain is generally considered to be 32mg daily– Some suggest TID – QID dosing but this is not clearly supported in the literature

Butrans® – Ratio estimated to be 1mg TD buprenorphine = 70-115mg PO morphine– Manufacturer’s guideline

MED < 30mg daily → Butrans ® 5mcg/hr MED < 30-80mg → Butrans ® 10mcg/hr MED > 80mg → caution advised

– Recommended to taper patients to < 30mg MED for up to 7 days prior to switching to Butrans®

– Maximum dose is 20mcg/hr due to QTc prolongation

Heit HA et al. Clin J Pain 2008; 24:93-97McPherson ML. (2010). Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. Bethesda MD: American Society of Health-System Pharmacists

OPIOID DOSE LIMITING

What is the biggest risk factor for an opioid-related overdose

Green – opioid daily dose greater than 120mg MED

Pink – concurrent use of benzodiazepines/hypnotics

Purple – aberrant behaviors

Yellow – comorbid mental health disorders

Morphine Equivalent Dosage (MED)

Used to standardize opioid dosing with various agents

Multiple conversion tables available

This table is a compilation of multiple different sources

Drug Oral Equianalgesic Dose (mg)

Morphine 30

Buprenorphine 0.4 (SL)

Codeine 200

Fentanyl 15mcg/hr (TD)**

Hydrocodone 30

Hydromophone 7.5

Meperidine 300

Methadone 10**

Oxycodone 20

Oxymorphone 10

Tramadol 120

McPherson ML. (2010). Demystifying Opioid Conversion Calculations: A Guide for Effective Dosing. Bethesda MD: American Society of Health-System Pharmacists

Dose Limiting Recommendations

Washington State passed legislation requiring all patients prescribed more than 120mg MED daily to be followed/reviewed by a pain specialist– Several other states and organizations have also followed suit

The CDC also recommended that patients prescribed more than 120mg MED without substantial improvement should be referred to a pain specialist

American Academy of Neurology: “If daily dosing exceeds 80–120mg MED daily, consultation with a pain management specialist is recommended, particularly if pain and function have not substantially improved”

Leavitt SB. Do Higher Opioid Doses Increase Overdose Risks?. Accessed 11/171/15. http://updates.pain-topics.org/2010/02/do-higher-opioid-doses-increase.htmlCDC Unintentional Drug Poisoning in the United States. Accessed 11/16/15. www.cdc.gov/injuryFranklin GM. Neurology 2014; 83(14):1277-1284

Opioid Concerns

Prescription opioids caused 16,651 deaths in 2010

Substance-abuse admissionsincreased by 400% between 1998 and 2008

Prescription painkillers are the second most prevalent type of abused drug after marijuana

Jones CM et al. JAMA 2013; 309:657–659Okie S. N Engl J Med 2010; 363:1981-1985CDC Unintentional Drug Poisoning in the United States. Accessed 11/16/15. www.cdc.gov/injury

Dunn - Seattle HMO Study

Designed to determine the opioid overdose risk in patients (n=9940) who received 3+ opioid prescriptions within 90 days for chronic non-cancer pain, 1997-2005

Dunn K et al. Intern Med 2010; 152:85-92

<20mg 20-49mg 50-99mg* >100mg*0.00%

0.50%

1.00%

1.50%

2.00%

0.2% 0.3%

0.7%

1.8%

Annual Overdose Rate

Daily Opioid Dose (MED)

Perc

enta

ge

99.49%

0.45%0.06%

Use without a documented overdose

Non-fatal overdoses

Fatal overdoses

Dunn K et al. Intern Med 2010; 152:85-92

Dunn - Seattle HMO Study Percentage Breakdown

Most of the overdoses (78.4%) occurred among patients receiving less than 100mg MED

Dunn K et al. Intern Med 2010; 152:85-92

Opioid Dose (MED mg/day) Number of Overdoses Overall Overdose Percentages

0 6 11.8%

1-<20 22 43.1%

20-<50 6 11.8%

50-<100 6 11.8%

>100 11 21.6%

Dunn - Seattle HMO Study and 100mg MED Daily

Aberrant Behaviors

Almost half (25 of 51) of overdose patients were expressing some aberrant behavior:– Eight cases involved accidental excess ingestion of opioids– Six were suicide attempts– Three persons obtained additional opioids illicitly– Four patients applied extra fentanyl patches– Four patients noted some type of drug abuse

Opioid-related overdoses were elevated in the following patients– History of substance abuse treatment– History of depression

Dunn K et al. Intern Med 2010; 152:85-92

Non-opioids

Dunn – Seattle HMO Study– Sedative hypnotics prescribed for 74.4% of patients

Percentage of patients prescribed at least 45 days of sedative-hypnotics = 31.9%

– Benzodiazepines prescribed for 42.7% of patients– Muscle relaxants prescribed for 52.3% of patients

Dunn K et al. Intern Med 2010; 152:85-92

Bohnert - VA Study

Compared VA patients that died of an opioid overdose to a random 5% sample of patients that were treated with opioids during the same time period, FY2004 and FY2005 – 750 total deaths

Risk of fatal overdose = 0.04%

Opioid Dose (MED mg/day) Number of Overdoses Overall Overdose Percentages

0 243 40.0%

1-<20 44 7.3%

20-<50 108 17.8%

50-<100 86 14.2%

>100 125 20.6%

Bohnert et al. JAMA 2011; 305(13):1315-1321

Dose Limiting: Final Thoughts There does appear to be a higher risk of opioid overdose with

increased daily doses of opioids More than 75% of the total overdoses examined in both studies

were in patients prescribed LESS THAN 100mg MED daily– Bohnert demonstrated that 43.5% of the fatal overdoses in the VA population

were not prescribed opioids Focusing on dose alone does not appear to be the complete

answer

NALOXONE

What is the best indicator of an opioid-related overdose

Green – altered mental status

Pink – decreased heart rate

Purple – miotic (constricted) pupils

Yellow – decreased respiratory rate

Opioid Epidemic

Poisoning is the leading cause of injury related death in the US– Opioid deaths accounted for more than 55% of US poisoning deaths in 2013

Opioid analgesics – 16,235 Heroin – 8,257

The United Nations recognized overdose as a global public health issue

Hedegaard H et al. NCHS data brief, no 190. Hyattsville, MD: National Center for Health Statistics. 2015.Centers for Disease Control and Prevention (CDC). Morb Mortal Wkly Rep 2012; 61:101-5Walley AY et al. BMJ 2013; 346:f174

Naloxone

Naloxone is an opioid antagonist that reverses the effects of opioid overdose– Competes for the mu, kappa, and sigma opiate receptor sites in the CNS with

the highest affinity for the mu receptor– Reverses opioid overdoses only

From 1996-2014 an estimated 152,283 lay persons received Overdose Education and Naloxone Distribution (OEND) from 644 sites throughout the US– Resulted in 26,453 opioid overdose rescues

Warner M et al. NCHS Data Brief 2011; 81:1-8Product Information: NARCAN(R). Endo Pharmaceuticals Inc, Chadds Ford, PA, 2003.Wheeler E et al. MMWR Morb Mortal Wkly Rep. 2015 Jun;64(23):631-5.

Dosing

IV/IM/subQ: 0.4-2mg Intranasal: 2mg

– Dispensed with a mucosal atomizer device– Commercially available Narcan nasal spray, approved 11/19/2015

Adapt Pharma will price the medication at $37.50 per dose for all governments and public organizations, available Jan 2016

Evzio® auto-injector: 0.4 mg IM or subQ into thigh– Once activated, provides verbal commands for administration

Above doses can be repeated every 2-3 minutes If no response after 10mg, reconsider diagnosis of opioid toxicity

Product Information: NALOXONE HCl. Mylan Institutional LLC, Rockford, IL, 2014.Lavonas EJ et al Circulation 2015; 132(18 Suppl 2):S501-S518.Adapt Pharma Press Release. http://www.adaptpharma.com/press-releases. Accessed 11/18/2015. Product Information: EVZIO(TM). Kaleo, Inc., Richmond, VA, 2014.

Signs and Symptoms of an Opioid-related Overdose

Depressed mental status– Non-responsive to external stimuli (yelling, sternal rub, gentle shaking, pain)

Decreased respiratory rate (less than 12 breaths/minute)– Best predictor of an opioid-related overdose– Results in blue/purple cast to fingertips, fingernails or lips

Decreased heart rate Decreased bowel sounds Miotic (constricted) pupils

– Normal pupils does not exclude opioid intoxication: meperidine or coingestants

Stolbach A. Acute opioid intoxication in adults. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on November 16, 2015.)Coffin P. Prevention of lethal opioid overdose in the community. UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on November 16, 2015.)Hoffman JR. Ann Emerg Med 1991; 20(3):246

Response to Overdose

Attempt to arouse patient with a firm sternal rub If there is shallow or absent breathing administer naloxone Call 911 Perform rescue breathing Re-administer naloxone after 2-3 minutes if still non-responsive Stay with the patient for at least three hours or until help arrives Place person on his/her side to prevent aspiration after vomiting.

Coffin P. Prevention of lethal opioid overdose in the community. UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on November 16, 2015.)

Identifying Patients at Risk

No consensus on who should receive naloxone for overdose prevention History of a previous opioid overdose

– Strongest predictor History of a substance use disorder Higher the dose, higher the risk

– MED >100mg daily results in a 9-fold increase in risk of an overdose Presence of aberrant drug taking behavior Concurrent use of other sedatives or alcohol Recent abstinence Comorbid pulmonary disease and/or sleep apnea

Coffin PO et al. Acad Emerg Med 2007 Jul; 14(7):616-23Dunn K et al. Intern Med 2010; 152:85-92Bohnert et al. JAMA 2011; 305(13):1315-1321Darke S et al. J Urban Health. 2003 Jun; 80(2):189-200Chaparro LE. Spine. 2014 Apr;39(7):556-63

Overview of CO Naloxone Laws

SB 13-014 - provides protection from criminal charges for medical professionals who prescribe naloxone to third parties, and for non-medical people who witness an overdose and administer the drug. It protects healthcare professionals who administer naloxone in an overdose emergency from charges

SB 12-020 - encourage witnesses to call for medical help during emergency overdose situations. The law provides limited legal protection from drug charges for those who call 911 for help. It also protects persons suffering an opiate overdose

SB 15-053 - allows physicians to write standing orders for naloxone that can be dispensed by designated pharmacists (or harm reduction agencies)

Colorado Consortium for Prescription Drug Abuse Prevention. The Problem: Laws and Policies. Accessed 11/16/15. http://takemedsseriously.org/the-problem/laws-policies/

URINE DRUG SCREEN MONITORING

Which of the following patients should be selected for a urine drug screen

Green – 75yo grandmother prescribed zolpidem 5mg QHS + trazodone 50mg QHS PRN sleep

Pink – 21yo college student with a hx of Percocet overdose, but not currently prescribed any controlled medications

Purple – 44yo engineer prescribed morphine SR 30mg Q8H

Yellow – 55yo psychologist prescribed lorazepam 1mg TID PRN anxiety

Benefits

Urine drug screening (UDS) is a necessary tool for: – Confirming compliance with prescribed medications– Identifying the use of illicit substances

Random testing is more likely to detect surreptitious drug use UDS monitoring demonstrated improvement in identifying aberrant

drug taking behaviors versus clinical assessment alone Urine is preferred over blood or saliva for monitoring

Chou R et al. J Pain. 2009; 10(2):113Becker W et al. Prescription drug misuse: Epidemiology, prevention, identification, and management. In: UpToDate, Post TW (Ed), UpToDate, Waltham, MA. (Accessed on November 16, 2015.)Katz NP et al. Anesth Analg 2003 Oct; 97(4):1097-102Pesce A et al. Pain Medicine 2012; 13:868–885

Types

Immunoassay– The most common method for the initial screening process– Uses antibodies for substance detection– Large scale and fast results– Cost effective– Can result in false positive results

Gas chromatography–mass spectrometry (GC-MS)– Criterion standard for confirmatory testing– Can detect small quantities of a substance– Most accurate, reliable and sensitive method of testing– Time consuming– Costly– Generally reserved for confirmatory testing after an immunoassay screen

Moeller KE et al. Mayo Clin Proc 2008; 83(1)66-76

Detection Times

Moeller KE et al. Mayo Clin Proc 2008; 83(1)66-76

Who to Test

All chronic users of controlled substances– Opioids– Benzodiazepines– Hypnotics

Patients with a history of chemical dependency– Monitoring for abstinence– Indicator for chemical dependency referral

When to Test – Risk Stratification Model

Low Medium HighNo hx substance abuse Family hx substance abuse Hx substance abuse

Low opioid dose < 50mg MED Moderate opioid dose 50-100mg

High opioid dose > 100mg

No concurrent sedatives Concurrent sedatives + low opioid dose

Concurrent sedatives + moderate dose

No aberrant behaviors Expressing aberrant behaviors

No hx medication overdose Hx medication overdose

When to TestOnce yearly Twice yearly Four times yearly

Dunn K et al. Intern Med 2010; 152:85-92Bohnert et al. JAMA 2011; 305(13):1315-1321Coffin PO et al. Acad Emerg Med 2007 Jul; 14(7):616-23Darke S et al. J Urban Health. 2003 Jun; 80(2):189-200

Interpretation Pearls

PRN medications and negative results– Important to determine average daily dose and most recent use

Amphetamine– Multiple false positives, obtain confirmation screen

Methadone and fentanyl – Will not return a positive opiate screen, requires a specific screen

Oxycodone– Can be +/- on a screen depending on dose, may require confirmation

Heroin– 6-MAM metabolite has a short half-life (36min) and is typically only detectable up to 8hrs

after use Cocaine

– Few false positives via immunoassay, rarely requires confirmation

Moeller KE et al. Mayo Clin Proc 2008; 83(1)66-76Pesce A et al. Pain Medicine 2012; 13:868–885

Questions???