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 9 th - 13 th
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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.
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
– 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
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