Managing chronic and breakthrough pain with opioid analgesics Rollin M. Gallagher, MD, MPH Clinical Professor of Psychiatry and Anesthesiology Director, Center for Pain Medicine, Research and Policy University of Pennsylvania School of Medicine Director of Pain Management Philadelphia Veteran Affairs Medical Center [email protected]
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Managing chronic and breakthrough pain with opioid analgesics
Managing chronic and breakthrough pain with opioid analgesics. Rollin M. Gallagher, MD, MPH Clinical Professor of Psychiatry and Anesthesiology Director, Center for Pain Medicine, Research and Policy University of Pennsylvania School of Medicine Director of Pain Management - PowerPoint PPT Presentation
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Managing chronic and breakthrough pain with opioid
analgesics
Rollin M. Gallagher, MD, MPH
Clinical Professor of Psychiatry and Anesthesiology Director, Center for Pain Medicine, Research and Policy
University of Pennsylvania School of Medicine
Director of Pain ManagementPhiladelphia Veteran Affairs Medical Center
Secondary prevention: - when injuries or diseases occur, prevent or minimize nociception or neural activation of pain pathways with specific, targeted interventions and restore and maintain function
Tertiary prevention- manage perpetuating factors, control pain and restore function and quality of life
Over 30 years a major shift occurred in opinion about the use of opioids for chronic
pain
1) Emphasis on evidence, not opinion, in clinical medicine
2) Emphasis on cost-containment in managed systems: short-term solutions and cost-shifting
3) Documented clinical experience over several decades:- Cancer pain management- Rehabilitation of disabling back pain - Treatment of severe neuropathic pain (often failed
back surgery)
Over 30 years a major shift occurred in opinion about the use of opioids for chronic pain
4) Recognition that: poorly controlled pain damages the
nervous system and must be controlled pain as a chronic disease societal health burden of uncontrolled
pain exceeds, many fold, the burden of prescription drug abuse
5) Recognition that opioids are: * well-tolerated by many* generally safe (e.g., motor function, driving,etc),
compared to other medications for daily use for pain (e.g., in elderly)
7) The demonstration that NSAIDs and acetomenophen, and now Cox-IIs, are potentially dangerous
8) The recognition opioids are effective for pain diseases (e.g., neuropathic pain)
9) The recognition that use of opioids after painful injury may prevent chronic pain. (Secondary prevention)
10)The recognition that opioids for common chronically painful conditions in elderly may improve health outcomes
Over 30 years a major shift occurred in opinion about the use of opioids for chronic pain
Opioid protective effect Castillo et al Pain 124(2006),321-326
“Patients treated with narcotic medication for pain at three months post-discharge were protected against chronic pain, despite the fact that these patients had higher pain intensity levels and were thus at higher risk.”
“The results presented here appear to lend support to the theory that…
..early aggressive pain treatment may protect patients from central sensitization and chronic pain.”
DID ANY PATIENTS DEVELOP: HYPERALGESIA?
TOLERANCE? ADDICTION?
Opioid protective effect: Tertiary Prevention
• Study of 10,372 nursing home residents– patients appear to function better and more
safely when taking opioids for pain– presumably because with better pain control,
they are more ambulatory, stronger and less likely to fall
Therefore, under clinical conditions where dosing and use is monitored, such as in the
Won et al. J Gerontology. 2006; 61A(2):165-69.
EFFECTS OF THESE CHANGE IN PERSPECTIVE AND PRACTICE MODELS
• More opioids prescribed
• More patients obtaining pain relief
• More opioids in circulation
• The Opium Wars, circa 2006
Changes Opioid Prescribing1997-2001
• Morphine 143%
• Hydrocodone 173%
• Fentanyl 240%
• Methadone 350%
• Oxycodone 430%
• Meperidine -10%DEA ARCOS data
Percentage Drug Poisoning
Deaths
1999 (n=10,295)
2000 (n=10,811)
2001 (n=12,034)
2002 (n=15,125)
0%
10%
20%
30%
40%
50%
28.1%29.0%
33.1%36.5%
30.9%
28.0% 26.6% 25.8%16.7% 15.7%
13.6% 12.8%Heroin
Cocaine
Opioid Analgesics
30%
20%
10%
•
Percentage of U.S. Unintentional Drug Poisoning Deaths† from Opioid Analgesics, Cocaine, and
Heroin, 1999 to 2002*
OUR CONUNDRUM
Growing societal awareness of: 1. the prevalence of inadequately treated chronic pain 2. its impact on society3. the need for access to effective pain treatment
VS
Growing societal awareness of: 1. The rapidly increasing rate of use of opioid prescriptions2. The increasing rate of prescription drug abuse3. The increasing rate of prescription drug abuse deaths
1) When should I consider treating chronic pain with opioid analgesics?
2) What should guide selection of a long-acting opioid in the treatment of chronic pain?
3) How do I titrate opioid medications and evaluate effectiveness?
QUESTIONS
4) When and how should methadone be used in the treatment of chronic pain?
5) Should use opioids to treat patients with chronic pain who also have a substance abuse history?
6) How should I use treatment agreements?
7) When should I consider stopping opioid therapy in a patient who has been on opioids chronically? How should this be done?
Medication selection in pain is based upon more than just pain severity *
• Diagnosis
• Efficacy– Clinical trial data
• Mechanisms of pain (s)
• Co morbidities: medical and psychiatric
• Prior treatment responses
• Side effect burden, toxicity risk, and the need to maintain function
• Gallagher RM, Verma S. Sem Neurosurg 2004; 15(1):31-46.• Sindrup SH, Troels TS. Pain. 1999;83:389-400.• Galer BS. Neurology. 1995;45(suppl 9):S17-S25.
Efficacy Comparison, Neuropathic Pain: Numbers Needed to Treat Analyses
Capsaicin(Sindrup and Jensen, 1999)
Gabapentin(Rice and Maton, 2001)
TricyclicAntidepressants
(Raja et al, 2002)
Opioids(Raja et al, 2002)
LidocainePatch 5%
(Meier et al, 2003)
Gabapentin(Rowbotham et al, 1998)
Dru
g o
r Th
era
peu
tic C
lass
Number-needed-to-treat (NNT)Mean ±95% Cl
0 5 10 15 20
5.3
5.0
3.2
4.0
2.7
4.4
Meier et al. Pain. 2003;106:151–158
∞
Medication selection in pain is based upon more than just pain severity *
• Ease of use– dosing– titration– drug-drug interactions– patient acceptability
• Pain’s psychosocial context and the doctor-patient relationship:- stigma- cost- illness behavior- risk of treatment non-adherence- risk of medication misuse
• Gallagher RM, Verma S. Sem Neurosurg 2004; 15(1):31-46.• Sindrup SH, Troels TS. Pain. 1999;83:389-400.• Galer BS. Neurology. 1995;45(suppl 9):S17-S25.
Opioids have important advantages in the treatment of pain:
• Opioids relieve the subjective suffering component of pain, without interfering with basic sensation, such as light touch, pinprick, temperature, position.
• No ceiling effect• Actions reversible with antagonists
Patients often report:
“The pain is still there, but it doesn’t bother me”
Opioid Analgesics
What should guide selection of a long-acting opioid in the treatment of chronic pain?
Identify the kind of pain: Nociceptive pain Neuropathic pain Visceral pain Myofascial pain
Identify the pattern of the pain
Around-the-ClockMedication
Breakthrough Pain
Over Medication
Persistent
Pain
Time
What should guide selection of a long-acting opioid in the treatment of chronic pain?
THE PATTERN
CHOOSING MEDICATION
Expect partial effects
Use multiple agents with different mechanisms: - from different classes
- from the same class
Nociceptivepain
Neuropathicpain
Pain condition
Secondary sleepdisturbance
Secondary depression Primary
Depression
Short-termNSAIDs,
Cox-II (?),opioids
Persists afteradequateanalgesia
Persists afteradequateanalgesia
Evaluate risks
Evaluate risks
Antihistamine,zolpidem,low-dose
benzodiazepine
Trazodone
Low-doseTCA
Lidocaine patch;gabapentin & other
AED (Ca+ & Na+ channels); alpha 2 agonists
(tizanidine, clonidine);opioids
Titrate TCAs (Na+ channels and SNRI) :
desipramine, nortriptyline,
SSRI trial
Evaluate risksSNRIs: venlafaxine,
duloxetine
Algorithm for Medication Selection in Chronic Pain with and without Co-Morbid Depression
Gallagher RM, Verma S. Semin Clin Neurosurgery. 2004This information concerns uses that have not been approved by the US FDA.
Evaluate risks
What should guide selection of a long-acting opioid in the treatment of chronic pain?
LA morphine: provides sustained serum levels of active morphine - Q 8-12 hours (MS Contin)- Q 12-24 hours (Kadian)- Q 24 hours (Avinza)
LA oxycodone (Oxycontin): Q 8-12 hours [now manufactured by two companies]
Methadone Q 6-12 hours [also has NMDA effect specific for neuropathic pain]
Transdermal fentanyl patch: Q 48-72 hours
Variability Opioid Responsiveness
• Pain syndromes differ– Somatic versus neuropathic
• Different patients respond differently– Responsiveness may be genetically
mediated
• Drugs may vary in specific activity– Evidence of sub-mu receptors emerging– Incomplete cross tolerance suggests
variable sub-mu activities of different opioids
Genetic variability of morphine analgesia in
Mouse Strains
Strain Morphine (5 mg/kg)
CD-1 76%Swiss Webster 40%BALB/c 90%
C57/bgJ 62%C57/+ 40%HS 62%CXBK 0%Pasternak, G 2003
Opioid Analgesia in CD-1 and CXBK Mice
0
25
50
75
100
CD-1
An
alge
sia
(% o
f m
ice)
*P <.004**P <.001
Rossi GC, et al. Neurosci Lett. 1996;216:1-4.
Mor
phi
ne
M6G
Her
oin,
s.c
.
6AcM
or
Mor
phi
ne, s
.c.
(-)M
etha
don
e
Fen
tany
lAll drugs were given i.c.v., unless stated otherwise
6AcMor=6-acetylmorphine
CXBK
* **
Mor
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Mor
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.c.
M6G
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6AcM
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etha
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Courtesy, G Pasternak 2006
Who is likely to do well on LA opioids?
Level 3-4 evidence suggests that the following characteristics predict lower rates of aberrant behavior:
• Goal-directed, adherent to medical regimens, and functional
• Takes responsibility for health and multi-modality treatment
• Understands concepts in opioid use: tolerance, dependence (physical), addiction
Bloodworth D, Am J Phys Med & Reh 2005(S);84(3):S64
Who is likely to do well on LA opioids?
Level 3-4 evidence suggests that the following characteristics predict lower rates of aberrant behavior:
• Understands and accepts the need for treatment agreements
• Absence of severe, chronic psychopathology
• Absence of personality disorder
• Rarely overuses medication
• No illicit drug abuse or alcohol abuse
Bloodworth D, Am J Phys Med & Reh 2005(S);84(3)
Which characteristics might predict that a patient might require more structure?
1) Aberrant Behavior: The Opioid Renewal Clinic: A structured approach to managing opioids for pain in primary care
(Wiedemer et al PAIN MED 2007)
2) In pain and addiction co-morbidity, managing either addiction or chronic pain alone, without managing the other, is usually futile.
When and how should methadone be used in the treatment of chronic pain?
Advantages over other LA opioids moderate NMDA (N-methyl-D-aspartate) receptor
antagonist activity, such that in animal studies methadone attenuates the development of tolerance and hyperalgesia
theoretically methadone may reduce wind-up and sensitization that leads to tolerance and dosing escalation in neuropathic pain
Advantage over morphine lower potential for opioid-induced neurotoxicity lower mu-opioid-receptor affinity absence of active metabolites
Methadone
• Not prone to conversion to a SA opioid by crushing, as are LA morphine and oxycodone preparations
• Relatively graduated onset of action reduces the likelihood of a psychoactive effect.
Methadone’s disadvantages
• Stigmatization due to long association with the treatment of heroin addiction
• Inexactness of equivalency tables due to the variability of methadone metabolism: SAFETY ISSUE
• Interactions with other medications due to metabolism by the type I cytochrome P450 (CYP450) group of enzymes - fluoxetine directly inhibit CYP3A4, reducing elimination of methadone - venalafaxine has the lowest probability of interaction with methadone, only
marginally inhibiting CYP1A2
• May require three or four times daily dosing for pain control
Pharmacokinetic & Pharmacodynamic Properties
• Long and variable half-life (15 to 150 hours)
• Elimination half-life does not reflect duration of analgesia
• Onset of action 1-2 h
• Peak effect 3-4 h
• Steady state 5-7 days
• Analgesic effect - approx 6 to 8 hours
Points to consider regarding equianalgesic conversion ratios
Due to inter-individual variability in hepatic metabolism of methadone and potential interactions with other meds:
• Equianalgesic conversion ratios are imprecise
• Contrary to logic, methadone appears to be more potent when changing from high doses of other opioids, thus there are dose dependent conversion ratios.
• Equianalgesic conversion ratio is only one factor in properly dosing methadone or any other opioid. Use the conversion table to get an idea of what the end point of titration might be. It is often lower but depends on many variables.
Dosing Strategies
• Overall strategy: start low and go slow• Opioid naive or on low dose of current opioid
– Stop current opioid– Start low : generally 2.5 to 5 mg– Start with one dose or BID on day one.– If tolerated increase to q 6 to 8 hours over the next 2 to 4 days, hold
at this level for 5 to 7 days then start with the incremental increases as listed below.
– Each 6 or 8 hourly dose may be increased by 2.5 to 5 mg increments every 5 to 7 days
• If the patient becomes sedated, hold increasing dose until tolerance to sedation develops
• Once adequate analgesia has been achieved, the same daily dose can be given in divided doses every 8 or 12 hours
Patient education highlights
a. Explain that initial dose will often be inadequate for pain relief
b. Reassure that the dose will be titrated to adequate analgesia
c. Explain that analgesic effect of methadone will probably be felt toward the end of the first week
d. Address the stigma of use in heroin addiction up front. Methadone was a pain medication before a heroin addiction medicine !
e. It is " different" than what is used for heroin addiction- it is a pill, not a liquid
Methadone and Torsade de Pointes
• Methadone is used daily by > 180,000 Americans.
• The literature reports 17 cases of torsades.
• Of the 17cases, 10 patients were on other contributing drugs and most were on doses > 100 mg/day.
Methadone and Torsade de Pointes
Recommendations:• Titrate methadone slowly; Monitor patient for
dizziness, lightheadedness, palpitations.• Monitor ECG in patients with risk factors (i.e. on
medications that have torsades potential)
• DO NOT use in patients with:- Prolonged QT- Recent conversion from atrial fibrillation- Family history of sudden death
When to stop opioid in a patient
• If they have adverse reactions to opioids, such as depression or respiratory depression.
• If they do not achieve reasonable therapeutic goals such as improved physical or social functioning, even with effective pain relief.
When to stop opioid in a patient
• If they do not adhere to other prescribed treatment that is necessary for a desirable treatment outcome
• If they exhibit persistent aberrant behavior and are unable to responsibly manage opioids within the constraints of a treatment agreement.
• If they are diagnosed with an addiction disorder and refuse referral for its treatment.
How to taper opioids?
1) Discuss with the patient and other responsible persons who may be or helpful.
2) Reassure patient and SO of alternative plan for pain control.
3) Patients with aberrant behavior or addiction may refuse to comply and leave treatment, seeking opioids elsewhere.
4) Document discussions and provide a written treatment plan that is given to the patient.
How to taper opioids?
4) The speed depends on the clinical circumstances.
A slow taper can be done by reducing the dose by 10 % every two weeks or even longer.
A more rapid taper can be accomplished but may require additional medical management of withdrawal symptoms.
5) An alpha 2 agonist such as clonidine can be used to help medically stable patients manage withdrawal symptoms. Some advocate gabapentin as well.
How to taper opioids?
6) Patients and their significant others need to know what to expect – discomfort, anxiety, restlessness, nausea, sweating, etc. – but that controlled withdrawal from opioids is not dangerous in and of itself.
7) If the patient is taking a sedative or benzodiazepine, these should be maintained, as their withdrawal is more difficult and dangerous.
SUMMARY: Using opioids in pain medicine
Generate:a) hypotheses about pain diagnosis and mechanismsb) a biopsychosocial formulation of painc) Identify risk factors for opioid use
Prioritize a problem list for each patient, identifying immediate, pivotal and background biopsychosocial problems.
Use evidence-based algorithms to treat different types of pain
Identify functional outcome goals for treatment
SUMMARY: Using opioids in pain medicine
Gradually titrate short acting opioids to effects
Replace with Long Acting Opioid to equivalent dose
Provide limited amounts of Short Acting Opioids for breakthrough pain
Train patient to use other behavioral and physical techniques to manage pain:
• Personality traits – manageable with structure and behavioral contracts• Oppositional personality: “I’ll do it my way”• Type A personality: “I must win at all costs”
• Dementia / delerium causing forgetfulness - manageable with environmental structure and support
The John Wayne SyndromeThe John Wayne Syndrome
• Bite the bullet
• Be tough
• Asking for painkillers is a
sign of weakness
• Long-suffering hero
• “Holing up”
• Gastric CA in a tough guy
Causes of difficult behavior
1) Non-adherence to prescribed regimen
• Clinical syndromes causing disorganized behavior – treatable with meds and psychotherapies• “Disorganized personality” – ADHD• Clinical depression: major, minor,
dysthymia• Anxiety disorder: GAD, Panic
Causes of difficult behavior
2) ABERRANT BEHAVIOR ON OPIOIDS (early refill calls, lost prescriptions, etc) – behavioral agreements / contract