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The Use of Opioids for Chronic Non‐Cancer Pain
Binit J. Shah, MD
Senior Instructor, Departments of Anesthesiology & Psychiatry
University Hospitals Case Medical Center
Cleveland, OH
Disclosures
• Boston Scientific: consultant
• Oxford University Press: pre‐publication book reviewer
• AllMed: utilization review, physician peer review
Objectives
• State of opioid prescribing
• Efficacy for chronic non‐cancer pain (CNCP) & side effects
• Addiction: definitions
• Opioid risk stratification & monitoring
The Opium Poppy
Nomenclature
• Opium: dried powdered mixture of 20 alkaloids from the seed capsules of the poppy
• Opiate: any agent derived from opium (really only 3: codeine, morphine, thebaine)
• Opioid: all substances with morphine like properties
We are a culture of pill takers….
• Americans are only ~5% of the world’s population, yet we use 80% of the world’s opioid supply, 99% of the world’s hydrocodone supply and 66% of the world’s illicit drugs.1
1. Solanki DR, Koyyalagunta D, Shah RV, et al. Monitoring opioid adherence in chronic pain patients: assessment of risk of substance misuse. Pain Phys 2011:14:E119‐31
Opioid Use ‐ Statistics
• 15% of chronic pain patients not treated with opioids had illicit drug use vs. 34% illicit drug use in patients treated with opioids.1
• Are patients with substance abuse are more likely to request & be prescribed opioids?
• Are patients prescribed opioids are more likely to develop co‐morbid substance abuse issues?
1. Christo PJ, Manchikanti L, Ruan X, et al. Urine drug testing in chronic pain. Pain Phys 2011;14:123‐43
Opioid Overdose
• From 2004 to 2008 the estimated number of emergency department visits linked to the nonmedical use of prescription pain relievers rose from 144,644 visits to 305,885 visits a year.1
• Methadone was 2% of painkiller prescriptions in the United States in 2009, but was involved in >30% of prescription painkiller overdose deaths.2 ‐ 4/10 overdose deaths from a single prescription painkiller involved methadone ‐ 6x as many people died of methadone overdoses in 2009 vs 1999 1) http://www.cdc.gov/media/pressrel/2010/r100617.htm 2)http://www.cdc.gov/media/releases/2012/p0703_methadone.html
Tremendous Increase in Prescribing
• From 1997 to 2007, the milligram‐per‐person use of prescription opioids in the U.S. increased from 74 milligrams to 369 milligrams
‐ ↑ 402%
• In 2000, retail pharmacies dispensed 174 million prescriptions for opioids; by 2009, 257 million prescriptions were dispensed
‐ ↑ 48% http://www.whitehouse.gov/ondcp/prescription‐drug‐abuse
Who is Prescribing These Meds?
• 90% of patients are on opioids prior to presenting to a pain center.1
• Main prescribers of opioid analgesics are PCPs, followed by dentists and orthopedic surgeons. The main prescribers for patients age 10‐19 are dentists.2
1.
Manchikanti L, Damron KS, McManus CD, et al. Patterns of illicit drug use and opioid abuse in patients with chronic pain at initial evaluation: a prospective, observational study. Pain Phys 2004;7:431‐7. 2.
2. Volkow ND, McLellan TA. Curtailing diversion and abuse of opioid analgesics without jeopardizing pain treatment. JAMA 2011;305(13):1346‐7 PCP Prescribing Habits
• A 2012 study on PCP prescribing (N=61 PCPs) of pain meds to high risk patients showed that most reported low confidence and satisfaction levels in treating chronic pain. ‐ Despite this fact the majority (67.2%) were “highly likely” to prescribe opioids to patients with active substance use.
Vijayaraghavan M, Penko J, Guzman D, et al. Primary care providers’ views on chronic pain management among high‐risk patients in safety net settings. Pain Med 2012;13:1141‐8. PCP Prescribing Habits
• In a 2012 study of 38 PCPS who treat high‐risk patients, only 42.9% used an opioid agreement when prescribing to patients with a history of substance abuse. Penko J, Mattson J, Miaskowski C, et al. Do patients know they are on pain medication agreements? Results from a sample of high‐risk patients on chronic opioid therapy. Pain Med 2012;13:1174‐80. PCP Prescribing Habits
• PCPs were assessed regarding how well they follow nationally accepted pain treatment guidelines before and after 2‐hour intervention
• What % of PCPs discussed….
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Comorbid depression
Functional status
Substance use
Side effects
35% →
38% →
25% →
14% →
44%
49%
34%
20%
Corson K, Doak MN, Denneson L, et al. Primary care clinician adherence to guidelines for the management of chronic musculoskeletal pain: results from the study of the effectiveness of a collaborative approach to pain. Pain Med 2011;12:1490‐1501.
Whatever they’re called, at least they work…
• In a large epidemiologic study in Denmark, chronic pain patients using opioids had worse pain, higher health care utilization and lower activity levels than matched chronic pain patients not using opioids.1
• Opioid use may go against important principles of chronic pain management including increased self‐
efficacy, reduced reliance on the health care system, reinforcement of pain behavior, and passivity and loss of autonomy by externalization of the locus of control.2
1.
Eriksen J, Sjogren P, Bruera E, et al. Critical issues on opioids in chronic non‐cancer pain: an epidemiological study. Pain 2006;125:172‐9. 2.
Large RG, Schug Sa. Opioids for chronic pain of non‐malignant origin‐ caring or crippling? Health Care Anal 1995;3:5‐11.
…or maybe not.
• A systematic review of randomized trials for multiple opioids utilized for managing various chronic pain conditions, showed fair evidence for tramadol in managing osteoarthritis. For all other conditions and all other drugs excluding tramadol, the evidence was poor
based on either weak positive evidence or indeterminate or negative evidence. Manchikanti L, Ailinani H, Koyyalagunta D, et al. A systematic review of randomized trials of long‐term opioid management for chronic non‐cancer pain. Pain Phys 2011;14:91‐121. Myths & Facts (www.responsibleopioidprescribing.org)
Myth:
Chronic opioid therapy is supported by strong evidence
Physical dependence only occurs with high doses over months
High dose (≥120 mg of morphine/day) therapy is supported by strong evidence
Fact:
Evidence of long‐term efficacy is limited and of low quality
With daily use, dependence can occur in days or weeks
No randomized trials show long‐term effectiveness in CNCP
Opioids – side effects
• Opioid‐induced constipation is the most common side effect occurring in 40‐95% of patients.1
• Nausea occurs in 25% (less common in men), sedation in 20‐60% and pruritus in 2‐10%.2
• Opioids decrease total sleep time, sleep efficiency, delta sleep, REM sleep and increase time spent in light sleep.1
1.
Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Phys 2008;11:S105‐S120 2.
Swegle JM, Logemann C. Management of opioid‐induced adverse effects. Amer Fam Phys 2006;74(8):1347‐54. Opioids & immunosupression
• Opioid use in >65 is associated with 3x ↑ risk of pneumonia.1
• With the exception of methadone and tramadol, opioids have been shown to be immunosupressive.2
• Opioids exacerbate immunosuppresion in persons with HIV and may increase viral load.3
1. Dublin S, Walker RL, Jackson ML, et al. Use of opioids or benzodiazepines and risk of pneumonia in older adults: a populations‐based case‐control study. Journal of the American Geriatrics Society, Sept 2011 2. Pacifici R, Patrini G, Venier I, et al. Effect of morphine and methadone acute treatment on immunological activity in mice: pharmacokinetic and pharmacodynamic correlates. J Pharmacol Exp Ther 1994;269:1112‐6. 3. Peterson PK, Sharp BM, Gekker G, et al. Morphine promotes the growth of HIV‐1 in human peripheral blood mononuclear cell cocultures. AIDS 1990;4:869‐73.
Opioid‐induced Endocrinopathy (OIE)
• Hypothalamic‐pituitary‐gonadal Axis
₋ Hypothalamus  GNRH  anterior pituitary  FSH & LH  gonads (testes/ovaries)  testosterone & estradiol
• Opioids bind in the hypothalamus ↓ pulsatile release of GNRH  ↓ LH & FSH
• Signs/symptoms of hypogonadism
₋ Decreased libido, fatigue, depressed mood, hot flashes, loss of muscle mass, infertility, osteroporosis, erectile dysfunction, abnormal menses OIE
• Study: 88 males with CNCP on opioid medications, 44% had osteopenic or osteoporotic bone density and 27% were hypogonadal.1
• Study: 54 males with CNCP on long‐acting opioids vs 27 healthy controls, total testosterone was low in 74% of the opioid group.2
₋ Of men who reported normal erectile function before opioid use, 87% had severe erectile dysfunction
1.
Fortin JD, Bailey GM, Vilensky JA. Does opioid use for pain management warrant routine bone mass density screening in men?. Pain Phys 2008;11:4:539‐541. 2.
Daniell HW. Hypogonadism in men consumning sustained‐action oral opioids. J Pain. 2002;3:377‐384
Opioid‐induced Hyperalgesia (OIH)
• The condition in which opioids result in increased pain levels
• OIH was first recognized in the 1800s, and that fact that morphine could result in increased pain was observed by Albutt in 1870.1
• OIH typically produces diffuse pain, less defined in quality, that extends beyond areas of pre‐existing pain. It is worsened with increasing opioid doses.
1. Albutt C. On the abuse of hypodermic injections of morphia. Practitioner 1870;5:327‐31.
OIH
• Patients with chronic low back pain treated with long‐acting morphine developed hyperalgesia
within 1 month of starting treatment.1
• Observational study in patients taking methadone or morphine for CNCP, both groups developed hyperalgesia.2
• Patients on opioids who were scheduled for an interventional treatment reported more pain than those not on opioids.3
1. Chu LF, Clark DJ, Angst MS. Opioid tolerance and hyperalgesia in chronic pain patients after one month of oral morphine therapy: a preliminary prospective study. J Pain 2006;7:43‐8. 2. 2. Hay JL, White JM, Bochner F, et al. Hyperalgesia in opioid‐managed chronic pain and opioid‐dependent patients. J Pain 2009;10;316‐22. 3. 3. Cohen SP, Christo PJ, Wang S, et al. The effect of opioid dose and treatment duration on the perception of a painful standardized clinical stimulus. . Reg Anesth Pain Med 2008;33:199‐206.
How are opioids addicting?
• Opioids activate pre‐synaptic GABA neurons in the ventral tegmental area of the midbrain, inhibiting the release of GABA. • This disinhibits (GABA tonically inhibits dopamine release here) dopaminergic neurons allowing extra dopamine in the nucleus
accumbens stimulating the reinforcing effects
Nucleus Accumbens (in red):
area of brain responsible for
euphoria/reinforcing effects of opoids
Addiction
• In CNCP, rates were believed to be 2‐18%.
• July 2011 study assessed rates of opioid abuse/dependence using both DSM‐IV and proposed DSM‐V criteria in CNCP:
35%
Boscarino JA, Rukstalis MR, Hoffman SN. Prevalence of prescription opioid‐use disorder among chronic pain patients: comparison of the DSM‐5 vs. DSM‐4 diagnostic criteria. Jour of Add Dis 2011;30:185‐94. Opioid Effects: Tolerance
Two forms:
• Increased amount of substance to achieve the same effect
• Decreased effect with the same amount of substance used over a period of time
May be positive or negative
Tachyphylaxis: an acute (sudden) decrease in the response to a drug after its administration
• EX: LSD
Opioid Effects: Withdrawal
• Development of a set of symptoms when the substance is removed (usually acutely) or prevented from being used.
• Withdrawal symptoms do not indicate tolerance and do not indicate addiction.
₋ Examples: ₋ All opioids taken chronically produce physiological dependence that includes tolerance and withdrawal
₋ SSRIs – widely known not to be associated with tolerance or addiction
Addiction
• Addiction is a primary, chronic disease of brain reward, motivation, memory and related circuitry.
• Dysfunction in these circuits leads to characteristic biological, psychological, social and spiritual manifestations.
• This is reflected in an individual pathologically pursuing reward and/or relief by substance use and other behaviors. • (American Society of Addiction Medicine)
ABCDE’s of Addiction
• Inability to completely Abstain
• Impairment in Behavioral control
• Craving
• Diminished recognition of significant problems
• A dysfunctional Emotional response
4 C’s of Addiction
• Loss of Control over use
• Continued use despite negative Consequences
• Compulsive use
• Craving
Substance Abuse
A maladaptive pattern of substance use  1
within a 12‐month period:
• Failure to fulfill major role obligations
• Recurrent use in conditions which are physically hazardous
• Substance‐related legal problems
• Continued use despite social/interpersonal problems
American Psychiatric Association. (2000).Diagnostic and statistical manual of mental disorders (4th
ed., text rev.). Washington, DC
Substance Dependence
A maladaptive pattern of substance use  3 within a 12‐
month period:
• Tolerance
• Withdrawal
• Taking substance in larger amounts or for longer periods than intended
• Persistent desire or unsuccessful efforts to cut down
• Great deal of time spent obtaining, using or recovering from substance
• Social/recreational/occupational activities are given up
• Continued use despite knowing it is a problem
American Psychiatric Association. (2000).Diagnostic and statistical manual of mental disorders
(4th ed., text rev.). Washington, DC
Pseudoaddiction
A state in which the patient displays drug‐
seeking behavior due to an untreated or poorly treated underlying condition. When appropriate treatment is given, drug‐seeking behaviors resolve.
• Opioid seeking for true untreated pain
• Benzodiazepine seeking for anxiety
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Ex: 49 yo WF with Stage IV squamous cell carcinoma of tongue. Using lorazepam 1mg 6x/day and asking for more
Titrated to mirtazepine 30mg QHS and clonazepam 1mg BID with resolution of anxiety and benzodiazepine‐seeking.
Assessing Addiction Risk in Chronic Pain where Opioid Therapy is Being Considered
• Evaluation should be done before a patient is prescribed any opioids including history/physical examination, laboratory analyses, urine toxicology screen, check state prescription drug monitoring program
• Understand general risk factors
• Understand aberrant behaviors
• Utilize a validated tool to assess opioid misuse risk
• Render recommendation for treatment type and monitoring
Risk factors for Opioid Abuse
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Family history of alcohol, illicit or prescription drug abuse
History or preadolescent sexual abuse
History of mental illness
Legal/arrest history
Personal history of alcohol, illicit or prescription drug abuse
Psychological stressors (relationship issues, financial difficulties)
Current illicit drug or alcohol abuse
Tobacco abuse
Unrealistic expectations from opioid use (100% pain relief, resumption of all life activities without modification)
Younger age
Aberrant Behaviors
• Increasing dose of medication without clinician recommendation
• Abnormal results on UDS (presence of illicit drug metabolites, no evidence that the drug you are prescribing is present, high levels of ethyl glucuronide)
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Injecting or smoking oral medications
Selling medications
Forgery to obtain medications
Simultaneously obtaining controlled medications from multiple providers
Aberrant Behaviors (cont.)
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Going to ED for opioid medication refills
Requesting early refills
Reporting lost or stolen prescriptions
Not following up with appointments that do not involve dispensing opioids
• Motor vehicle accidents or arrests
• Abuse of illicit substances
• Reporting relief only from opioid medications
Aberrant Behavior
• Aberrant behaviors are found in up to 40% of patients prescribed opioid medications.
• The most predictive risk factor for abuse is a personal history of substance abuse
Opioid Risk Tool (ORT)
• 5 item tool validated in chronic non‐cancer pain patients to assess risk for aberrant behaviors.
• Scored by the clinician
• Assesses: family history of substance abuse, personal history of substance abuse, age (<45), history of pre‐adolescent sexual abuse and psychological diseases as risk factors
• Classifies patients into risk categories of low, medium & high
and give monitoring recommendations
• See PCSS‐O Opioid Prescribing Phone App to get an electronic version of the ORT that will score an individual’s risk
Webster LR, Webster RM. Predicting aberrant behaviors in opioid-treated patients: preliminary
validation of the opioid risk tool. Pain Med 2005;6(6): 432-42
How to Think About Monitoring Based on Risk Level
Low
Moderate
High
% with aberrant
behavior at 1 year
5%
28%
90%
Frequency of visits
Monthly
Biweekly
Weekly
Yes
Yes
Yes
Other UDS
Randomly
Every visit
Every visit
Pill Counts?
No
Consider
Yes
Referral to
psychiatry/addiction?
No
Consider
Yes
UDS at initiation?
Screener and Opioid Assessment for Patients with Pain‐Revised (SOAPP‐R) •
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Predicts possible opioid abuse in chronic pain patients
5‐10 minutes to administer (filled out by the patient)
24 items
Free to use, comes with self‐scoring (www.painedu.org) (but you will be asked to register with painedu if you wish to use this instrument)
• Sum the score of all items. ‐ ≥ 22 high risk
‐ 10 – 21 moderate risk
‐ < 9 low risk
Which Screening Method to Use?
2012 study compared psychologist screen vs ORT vs SOAPP‐r at 1 year for patients who were subsequently discharged1
• Psychologist screen was most predictive of discharge and a combination of psychologist + at least one screening tool gave the best sensitivity/specificity.
• This study does not imply that a psychologist must screen patients, but underscores that need that an experienced clinician screen patients
1. Jones T, Moore T, Levy JL, et al. A comparison of various risk screening methods in predicting discharge from opioid treatment. Clin J Pain 2012;28(2):93‐100.
Tips: Outpatients
• Discuss openly the need for frequent visits
• Phrase it in terms of concern/safety
• Tell patients at the first visit of the expectation that they will cooperate with urine drug screens
• Inform them that like all medications, use of opioids will be a trial.
• Determine your own threshold/endpoint of opioid dosing and discuss with the patient at the first visit.
• Document, document, document
Tips: Inpatient
• Less is more
₋ Frequent (daily) visits lead to repeated conversations and “battles” regarding opioid escalation
• Inform the patient that if they do not agree with the treatment plan, there are other facilities they can freely choose
• Remember, YOU are in charge of treatment not the patient
So, for those on Opioids: •
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Necessary to screen for mental illness
Necessary to screen for substance use
There are significant rates of addiction (~1/3)
There is little evidence for efficacy particularly at high doses (> 100 morphine equivalents daily or for long term (most studies have been conducted for 90 days or less))
• If mental disorder(s) or substance use disorder(s) are identified patient needs to receive treatment for conditions—either by you or a clinician/program to which you refer
• Consider safety/effectiveness of ongoing opioid therapy in these situations and document basis for any revisions in treatment plan and ongoing treatment recommended
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