Hot Topics in Chronic Pain Management:
Questions Every Pain Pharmacist is Asked
William D. Gersch PharmD, BCPS
Clinical Pharmacy Specialist – Pain Management
Kaiser Permanente Colorado
Colorado Pharmacists Society
2016 Winter CE and Ski Seminar
January 9th - 13th
Conflict of Interest Disclosure
I have no conflicts of interest to disclose.
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; 57:192–196
Sporer KA. Ann Emerg Med 2004; 43:580–584
Raisch DW et al. Ann Pharmacother 2002; 36:312–321.
Pergolizzi JV et al. Acta Anaesthesiol Taiwan 2015; 53(2):71-6
Sacerdote 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/expensive
Ohtani M et al. J Pharmacol Exp Ther 1995; 272:505–510
EMCDDA. 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; 24:93-97
McPherson 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 opioidrelated 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)
Drug
Oral Equianalgesic
Dose (mg)
Morphine
30
 Multiple conversion tables
available
Buprenorphine
0.4 (SL)
Codeine
200
 This table is a compilation of
multiple different sources
Fentanyl
15mcg/hr (TD)**
Hydrocodone
30
Hydromophone
7.5
Meperidine
300
Methadone
10**
Oxycodone
20
Oxymorphone
10
Tramadol
120
 Used to standardize opioid
dosing with various agents
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.paintopics.org/2010/02/do-higher-opioid-doses-increase.html
CDC Unintentional Drug Poisoning in the United States. Accessed 11/16/15. www.cdc.gov/injury
Franklin GM. Neurology 2014; 83(14):1277-1284
Opioid Concerns
 Prescription opioids caused
16,651 deaths in 2010
 Substance-abuse admissions
increased 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; 309:657–659
Okie S. N Engl J Med 2010; 363:1981-1985
CDC 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 noncancer pain, 1997-2005
Annual Overdose Rate
Percentage
2.00%
1.00%
0.50%
0.00%
Dunn K et al. Intern Med 2010; 152:85-92
1.8%
1.50%
0.7%
0.2%
<20mg
0.3%
20-49mg 50-99mg* >100mg*
Daily Opioid Dose (MED)
Dunn - Seattle HMO Study
Percentage Breakdown
Use without a documented
overdose
Non-fatal overdoses
99.49%
Fatal overdoses
0.51%
0.06%
0.45%
Dunn K et al. Intern Med 2010; 152:85-92
Dunn - Seattle HMO Study and 100mg MED Daily
 Most of the overdoses (78.4%) occurred among patients receiving
less than 100mg MED
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 K et al. Intern Med 2010; 152:85-92
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; 61:101-5
Walley 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; 81:1-8
Product 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):616-23
Dunn K et al. Intern Med 2010; 152:85-92
Bohnert et al. JAMA 2011; 305(13):1315-1321
Darke S et al. J Urban Health. 2003 Jun; 80(2):189-200
Chaparro 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 nonmedical 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):113
Becker 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):1097-102
Pesce 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
High
No hx substance abuse
Family hx substance abuse
Hx substance abuse
Low opioid dose < 50mg MED
Moderate opioid dose 50100mg
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 Test
Once yearly
Dunn K et al. Intern Med 2010; 152:85-92
Bohnert et al. JAMA 2011; 305(13):1315-1321
Coffin PO et al. Acad Emerg Med 2007 Jul; 14(7):616-23
Darke S et al. J Urban Health. 2003 Jun; 80(2):189-200
Twice yearly
Four times yearly
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)66-76
Pesce A et al. Pain Medicine 2012; 13:868–885
Questions???