Managing chronic and breakthrough pain with opioid analgesics

1
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
• rgallagh_at_mail.med.upenn.edu

2
PRINCIPLES OF TREATMENTSummary

• Primary prevention
• - avoid injuries and diseases
• 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

3
Challenges of Providing Chronic Pain Care
Changing societal laws, customs, values, economies
4
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)
5
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)

6
Over 30 years a major shift occurred in opinion
about the use of opioids for chronic pain

• The demonstration that NSAIDs and acetomenophen,
  and now Cox-IIs, are potentially dangerous
• The recognition opioids are effective for pain
  diseases (e.g., neuropathic pain)
• The recognition that use of opioids after painful
  injury may prevent chronic pain. (Secondary
  prevention)
• The recognition that opioids for common
  chronically painful conditions in elderly may
  improve health outcomes

7
DOES EARLY TREATMENT HELP?

• 567 severe single extremity trauma patients
• Predictors of poor outcome before injury
  include
• Alcohol abuse 1 month before injury (Marker,
  depression substance abuse)
• Older age, lower education, low self efficacy
  (Gallagher et al Pain 1989)
• Predictors of poor outcome at 3 months
  post-injury
• Acute pain intensity, anxiety, depression and
  sleep disturbance

8
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?

9
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.
10
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

11
Changes Opioid Prescribing1997-2001

• Morphine 143
• Hydrocodone 173
• Fentanyl 240
• Methadone 350
• Oxycodone 430
• Meperidine -10
• DEA ARCOS data

12
Percentage of U.S. Unintentional Drug Poisoning
Deaths from Opioid Analgesics, Cocaine, and
Heroin, 1999 to 2002

• 30
• 20
• 10

13
OUR CONUNDRUM

• Growing societal awareness of
• 1. the prevalence of inadequately treated
  chronic pain
• 2. its impact on society
• 3. the need for access to effective pain
  treatment
• VS
• Growing societal awareness of
• 1. The rapidly increasing rate of use of opioid
  prescriptions
• 2. The increasing rate of prescription drug
  abuse
• 3. The increasing rate of prescription drug
  abuse deaths

14
New York Times MagazineJune 17, 2007, COVER
STORY

• When Is a Pain Doctor a Drug Pusher?
• By TINA ROSENBERG

15
QUESTIONS

• When should I consider treating chronic pain with
  opioid analgesics?
• What should guide selection of a long-acting
  opioid in the treatment of chronic pain?
• How do I titrate opioid medications and evaluate
  effectiveness?

16
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?
• When should I consider stopping opioid therapy in
  a patient who has been on opioids chronically?
• How should this be done?

17
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. 199983389-400.
• Galer BS. Neurology. 199545(suppl 9)S17-S25.

18
Efficacy Comparison, Neuropathic Pain Numbers
Needed to Treat Analyses
Lidocaine Patch 5 (Meier et al, 2003)
4.4
2.7
Opioids (Raja et al, 2002)
Tricyclic Antidepressants (Raja et al, 2002)
4.0
3.2
5.0
Gabapentin (Rice and Maton, 2001)
Capsaicin (Sindrup and Jensen, 1999)
5.3
8
15
20
0
5
10
Number-needed-to-treat (NNT) Mean 95 Cl
Meier et al. Pain. 2003106151158
19
Medication selection in pain is based upon
more than just pain severity

• Ease of use
• dosing
• titration
• drug-drug interactions
• patient acceptability
• Pains 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. 199983389-400.
• Galer BS. Neurology. 199545(suppl 9)S17-S25.

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Opioid Analgesics

• 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 doesnt bother
  me

21
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

22
What should guide selection of a long-acting
opioid in the treatment of chronic pain?THE
PATTERN
Over Medication
Around-the-ClockMedication
Breakthrough Pain
Persistent Pain
Time
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CHOOSING MEDICATION

• Expect partial effects
• Use multiple agents with different mechanisms
• - from different classes
• - from the same class

24
Algorithm for Medication Selection in Chronic
Pain with and without Co-Morbid Depression
Pain condition
Neuropathicpain
Nociceptivepain
Secondary depression
Primary Depression
Secondary sleepdisturbance
Evaluate risks
Persists afteradequateanalgesia
Evaluate risks
Persists afteradequateanalgesia
Short-termNSAIDs,Cox-II (?),opioids
SSRI trial
Evaluate risks
Evaluate risks
Lidocaine patchgabapentin other AED (Ca
Na channels) alpha 2 agonists
(tizanidine, clonidine)opioids
SNRIs venlafaxine, duloxetine
Antihistamine,zolpidem,low-dosebenzodiazepine
Trazodone Low-doseTCA
Titrate TCAs (Na channels and SNRI)
desipramine, nortriptyline,
Gallagher RM, Verma S. Semin Clin Neurosurgery.
2004 This information concerns uses that have not
been approved by the US FDA.
25
What should guide selection of a long-acting
opioid in the treatment of chronic pain?

• Establish the goals of treatment
• Pain relief and reduced suffering
• Improved functional capacity QOL
• Physical functioning
• Cognitive functioning
• Social functioning
• Role functioning

To do what? To think about what? To be with
and enjoy whom? To accomplish what?
26
Choices of LA opioid

• All preparations are mu opioid agonists.
• All opioids are effective.
• 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

27
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

28
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 6
2 CXBK 0
Pasternak, G 2003
29
Opioid Analgesia in CD-1 and CXBK Mice
Courtesy, G Pasternak 2006
30
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

31
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)

32
Which characteristics might predict that a
patient might require more structure?

• 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.

33
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

34
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.

35
Methadones 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

36
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

37
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.

38
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

39
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

40
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.

41
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

42
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.

43
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.

44
How to taper opioids?

• Discuss with the patient and other responsible
  persons who may be or helpful.
• Reassure patient and SO of alternative plan for
  pain control.
• Patients with aberrant behavior or addiction may
  refuse to comply and leave treatment, seeking
  opioids elsewhere.
• Document discussions and provide a written
  treatment plan that is given to the patient.

45
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.

46
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.

47
SUMMARY Using opioids in pain medicine

• Generate
• hypotheses about pain diagnosis and mechanisms
• a biopsychosocial formulation of pain
• 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

48
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
• Ice
• Stretch
• TENS
• Relaxation
• Avoidance
• Pacing

49
SUMMARY Using opioids in pain medicine

• If one opioid not tolerated, or loses
  effectiveness, switch to another
• If switching to methadone, start very low and go
  slow, and be aware of drug interactions
• Be patient and dont leave the patient short
• Empower and engage patient www.nationalpainfound
  ation.org

50
ABOVE ALL, MAINTAIN INTELLIGENT AND INFORMED
EMPATHY BE PATIENT

• If I can stop one heart from breaking
• I shall not live in vain
• If I can ease one life the aching
• Or cool one pain,
• Or help one fainting robin
• Unto his nest again,
• I shall not live in vain 
• Emily Dickinson

51
The Public Health Problem of Chronic Pain

• Causes
• lack of societal medical knowledge about
  chronic pain diseases and conditions
• primary prevention
• secondary prevention
• treatment
• education and training deficits
• social inequities in access to care
• ineffective organizational models of care

52

• Questions??

53
Does our system of medical care play a role in
creating difficult behavior in a patient with
chronic pain ?
Inadequate Care Pain / Frustration Central
sensitization Worsening pain
LOSSES Frustration - Fear- Demoralization-
Behavioral Changes Depression Worsening
Pain
TIME
54
Categories of difficult behavior

• NON-ADHERENT
• ABERRANT ON OPIOIDS
• ANGRY, DEMANDING
• ENTITLED / VIP
• PASSIVE
• SEDUCTIVE

55
Causes of difficult behavior

• Non-adherence to prescribed regimen
• Personality traits manageable with structure
  and behavioral contracts
• Oppositional personality Ill do it my way
• Type A personality I must win at all costs
• Dementia / delerium causing forgetfulness -
  manageable with environmental structure and
  support

56
The 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

57
Causes of difficult behavior

• 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

58
Causes of difficult behavior

• 2) ABERRANT BEHAVIOR ON OPIOIDS (early refill
  calls, lost prescriptions, etc) behavioral
  agreements / contract
• Undertreated pain
• Tolerance
• Addiction
• Personality traits
• Psychiatric co-morbidities

59
The tertiary, sequential care model
INJURY/SYMPTOM
Emergency Services
TIME
Primary Care
1
1
2
Specialty Office 1
2
(5)
4
(6)
TREATMENT FAILURES
Specialty Office 2
3
ALTERNATIVE TREATMENTS
Specialty Office 3
3
CHASING THE SYMPTOM THROUGH A REDUCTIONISTIC,
BIOMEDICAL MODEL
5
3
Specialty Office 4
4
4
Gallagher RM. Med Clin N Am 83(5) 555-585,
1999.
60
Cost vs Quality
Resource
Excess care
Best practice
Quality of care
61
Pain medicine and primary care community
rehabilitation model
INJURY/SYMPTOM
Multidisc- iplinary Pain Center
7
1
Emergency Services
PrimaryCare ClinicalAlgorithms
Community Support Services (PT, OT,
Voc, behavioral, pharmacy)
2
Sub-specialty Eval. mgmt.
Recurrent or persistent pain impairing function
(4)
3
5
Integrated Pain Medicine Eval Services Med.
trials, PT, Blocks, Behavioral mgmt.
6
3
Treatment Failure
6
Gallagher RM. Med Clin N Am 83(5) 555-585,
1999. .