Transcript Buprenorphine for Pain and for Addiction

Buprenorphine for Pain and
for Addiction
David A. Moltz, MD
MAPP Clinical Conference
April 30, 2010
I. Addiction and
Dependence
DSM IV
Substance Dependence
A maladaptive pattern of substance use, with 3 or more of:
• Tolerance
• Withdrawal
• Using larger amounts or for a longer time than intended
• Persistent desire or lack of control
• A great deal of time spent obtaining, using, recovering
from
• Important activities given up
• Continued use in spite of negative consequences
Addiction
 A chronic but treatable brain disease
characterized by
 loss of control
 compulsive use
 use despite known harm
 relapse
Dependence vs Addiction
• Addiction may occur with or without the
presence of physical dependence.
• Physical dependence results from the
body’s adaptation to a drug or medication
and is defined by the presence of
– Tolerance and/or
– Withdrawal
Opioid Use in a Household Survey
Population
• According to the 2002 National Survey
on Drug Use and Health : An estimated
4.4 million persons were current users of
pain relievers for nonmedical purposes.
• New non-medical pain reliever use more
than quadrupled from 1990 (628,000
new users) to 2000 (2.7 million new
users).
SOURCE: SAMHSA, 2002.
Neural circuitry of reward
 Present in all animals
 Produces pleasure for
behaviors needed for
survival:
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Eating
Drinking
Sex
Nurturing
Neural circuitry of reward
Altruism activates
the same circuitry
Meeks TW, Jeste DV. The
neurobiology of wisdom. Arch Gen
Psychiatry 2009;66(4):355-365
Addiction is not a disease
of the synapses alone
--Mark Publicker
II. Properties of
Buprenorphine
Definition of Terms
• Agonist
• Antagonist
• Affinity
• Intrinsic Activity
• Dissociation
Buprenorphine
 Novel opioid with both agonist and
antagonist properties
 Partial agonist at mu opioid receptor
 High affinity
 Low intrinsic activity
 Slow dissociation
 Antagonist at kappa receptor
Buprenorphine
• High affinity for mu receptors  ability to
compete with full mu agonists (such as
heroin) and to block their effects.
• Low intrinsic activity  feeling of wellbeing without full opioid effects
• Very slow dissociation rate  prolonged
therapeutic effects.
• Ceiling effect
Opiate Potency of Methadone, LAAM, and Buprenorphine
Slide courtesy of Laura McNicholas, MD, PhD, Univ of Penn.
100
90
80
70
% 60
Efficacy
50
40
30
20
10
0
Full Agonist
(Methadone)
Partial Agonist
(Buprenorphine
Antagonist
(Naloxone)
-10
-9
-8
-7
Log Dose of Opioid
-6
-5
-4
Blockade Effect
• Buprenorphine has tight binding to and slow
dissociation from opioid receptors. It produces a
blockade effect at the mu-opioid receptor so that
subsequently administered opioids do not
produce their full euphoric effect.
• It appears to produce less physical dependence
than a full opioid agonist (such as methadone),
and it may be easier to discontinue at the end of
medication treatment.
Advantages of a Partial Agonist
• Lower abuse potential
• Lower level of physical dependence
• Relative safety if ingested in overdose
quantities
• Weak opioid effects compared with
methadone.
Severity of Opioid-Withdrawal Symptoms after Abrupt Discontinuation of Equivalent Doses of
Heroin, Buprenorphine, and Methadone
Kosten T and O'Connor P. N Engl J Med 2003;348:1786-1795
Kappa antagonism
• In animal models of depression,
dynorphins (kappa agonists) increased
stress.
• Kappa antagonists relieve it.
• “Blockade of k-opioid receptors may have
therapeutic potential for the treatment of
depression.”
Shirayama Y, et al. Stress increases dynorphin immunoreactivity in limbic brain
regions and dynorphin antagonism produces antidepressant-like effects. J
Neurochemistry 2004;90: 1258-68
III. Buprenorphine for
Addiction
Drug Addiction Treatment Act of 2000
(DATA 2000)
• Expands treatment options to include both
the general health care system and opioid
treatment programs.
– Expands number of available treatment slots
– Allows opioid treatment in office settings
– Sets physician qualifications for prescribing
the medication
Beneficial Effects
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Blocks craving
Blocks opiate withdrawal
Does not produce a ‘high’
Blocks the effects of other opioids
Milder withdrawal than methadone
Stabilization of brain function
Anti-depressant / anti-anxiety effect
Beneficial Effects
 Significant enhancement in treatment
retention and in the quality of
participation
 Mainstreaming of opioid dependence
treatment with office-based practice
 Greater safety
 Lower diversion risk
Beneficial Effects
• Buprenorphine is as effective as moderate
doses of methadone.
• Partial agonist effects make it mildly
reinforcing, encouraging medication
compliance.
• After a year of buprenorphine + counseling,
75% of patients were retained in treatment
compared to 0% in a placebo + counseling
condition.
Cognitive Effects
• Available evidence in patients maintained on
buprenorphine indicates no clinically significant
disruption in cognitive and psychomotor
performance.
• “Long-term use…does not impair driving ability.”
Dagtekin O, et al. Assessing cognitive & psychomotor performance under long-term treatment with
transdermal buprenorphine in chronic noncancer pain patients. Anesth Analg 2007;105:1442-8
Suboxone
• Buprenorphine + naloxone
• Partial agonist + pure antagonist
• Naloxone is only active intravenously
• Will precipitate withdrawal in opioid-dependent
individuals
• Combination decreases diversion risk
IV. Buprenorphine and Pain
Pain Patients vs Addicted Persons
Risk Factors
• Psychosocial
• Genetic
• Drug-related
Pseudo-addiction
• “Drug-seeking behavior”
• Consequence of inadequate treatment of
pain
• May be indistinguishable from addictive
behavior
Effectiveness in Pain
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30-40 times more potent than morphine
Ceiling effect  high safety profile
Transdermal used extensively in Europe
“…transdermal buprenorphine provides
effective, sustained and dose-dependent
analgesia, irrespective of age.”
Pergolizzi J et al. Opioids & the management of chronic severe pain in the elderly: Consensus
statement of an international expert panel. Pain Practice 2008;8(4):287-313
Chronic Cancer Pain
• Transdermal buprenorphine vs. sustainedrelease morphine, with tramadol
supplementation.
• “The administration of transdermal
buprenorphine versus morphine resulted
in significant differences in the physical
pain (p=0.01), mental health (p=0.03) and
vitality (p=0.001).”
Pace, MC, et al. Buprenorphine in long-term control of chronic pain in cancer patients.
Frontiers in Bioscience 2007;(12):1291-1299
Post-Partum Pain
• Women stabilized on methadone or buprenorphine,
treated post-partum with opioids or ibuprofen as needed.
• Buprenorphine group decreased ibuprofen use over 5
days.
• Methadone group increased ibuprofen use.
Jones HE, et al. Management of acute postpartum pain in patients maintained on methadone or
buprenorphine during pregnancy. Am J Drug and Alcohol Abuse, 2009; 35:151-56
Neuropathic Pain
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30 patients with chronic painful neuropathy
Transdermal buprenorphine
Non-blinded study
40% had clinically meaningful pain relief
Penza P, et al. Short- and intermediate-term efficacy of buprenorphine TDS in chronic
painful neuropathies. J of the Peripheral Nervous System 2008;13:283-288
Managing Pain During
Buprenorphine Maintenance
• Supplement with NSAIDS
• Temporarily replace buprenorphine with opiates
• Override buprenorphine with opiates
• Divide +/or increase buprenorphine dose
Heit HA, Gourlay DL. Buprenorphine: New tricks with an old molecule for pain
management. Clin J Pain 2008; 24(2):93-97
Hyperalgesia
Hyperalgesia
• A decrease in the threshold to elicit pain
• A state of nociceptive sensitization
• Hyperesthesia
Allodynia
The generation of pain in response to lowintensity stimuli or stimuli that are not
normally painful.
Mechanisms of Hyperalgesia
• NMDA (glutaminergic)
• Dynorphin (kappa receptor agonist)
• Peripheral, spinal and central sensitization
• “More complexity than clarity”
Opioid-Induced Hyperalgesia
• May be activation of hyperalgesic systems
to counteract the analgesic effects of the
opioids
• Ex: Morphine activates NMDA receptors
and spinal dynorphin
• In withdrawal, the hyperalgesic system is
unopposed
Hyperalgesia and Tolerance
• May share mechanisms (eg,NMDA), but
they are clinically different
• Hyperalgesia is increased sensitivity to
pain
• Tolerance is decreased sensitivity to
opioids
Chang G, et al. Opioid tolerance & hyperalgesia. Med Clin N Am 2007;91;199-211
OIH and Tolerance
• Difficult to differentiate clinically
• OIH diffuse, generalized pain, often
different from pre-existing pain
• Stopping the opioid can differentiate
– Tolerance  more pain
– OIH  less pain
Treating OIH
• Minimize opioid dose using adjuvant
therapies
• Opioid rotation
• Methadone (NMDA antagonist)
• Buprenorphine
Pain reduction after detoxification
• 23 patients not getting benefit from highdose opioids
• No addictive behaviors
• 21 showed marked decrease in pain after
detoxification
• After weaning, 63% decrease in pain with
buprenorphine vs. 47% without
Baron MJ, McDonald PW. Significant pain reduction in chronic pain patients after
detoxification from high-dose opioids. J Opioid Management 2006;2(5):277-282
Neuropathic pain
• Buprenorphine relieves allodynia from
neuropathic pain
• Blocks hyperalgesia due to central
hypersensitization
• Kappa antagonist (blocks dynorphin)
• “Buprenorphine has been shown to have a
pronounced antihyperalgesic effect.”
Induru RR, Davis MP. Buprenorphine for neuropathic pain – Targeting hyperalgesia. Am J Hospice &
Palliative Med 2009:26 (6);470-3
Likar R. Transdermal buprenorphine in the management of persistent pain – Safety aspects.
Therapeutics & Clinical Risk Management 2006:2(1):115-125
Buprenorphine and OIH
• “Resolution of OIH usually follows quickly
during the maintenance phase with
buprenorphine.”
• “Buprenorphine may be unique in its ability
to treat chronic pain and possibly OIH”
Silverman SM. Opioid induced hyperalgesia: Clinical implications for the pain practitioner.
Prescription Opioid Addiction
Treatment Study (POATS)
• Opioid dependence
• 42% with co-existent chronic pain
• Overall, 49% substantially improved after
3 mo of buprenorphine
• Of those with chronic pain, 53%
substantially improved, and “many had
significant improvement in their pain.”
Weiss R. NIDA Blending Conference 4/22/10. www.NIDA.NIH.Gov
Coexistent Addiction and Pain
• Buprenorphine is ideal
• Treats addiction
• Treats pain
• Relieves hyperalgesia
Resources
• Clinical Guidelines for the Use of Buprenorphine
in the Treatment of Opioid Addiction.
SAMHSA/CSAT Treatment Improvement
Protocols. TIP 40.
• http://buprenorphine.samhsa.gov
• http://www2.aaap.org/buprenorphine
(For DATA training)