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:




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







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
•
•
•
•
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
•
•
•
•
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)
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