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

II. 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 compete with full

mu

 ability to agonists (such as heroin) and to block their effects. • Low intrinsic activity  feeling of well being without full opioid effects • Very slow dissociation rate  therapeutic effects. prolonged • Ceiling effect

Opiate Potency of Methadone, LAAM, and Buprenorphine

Slide courtesy of Laura McNicholas, MD, PhD, Univ of Penn.

100 90 80 70 60 50 40 30 20 10 0 -10 -9 -8 -7 -6 -5 -4 Log Dose of Opioid

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.

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.

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

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

Research Outcomes

• 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.

100

80 60 40 20

Urine Testing for Opioids

All Subjects LAAM 49%

40%

Buprenorphine Hi Methadone

39%

Lo Methadone

19%

0 1 3 5 7 9

Study Week

11 13 15 17

Adapted from Johnson, et al., 2000

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

Addiction is not a disease of the synapses alone

--Mark Publicker

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

Buprenorphine vs Morphine

• Chronic cancer pain • More effective than morphine for physical pain, mental health and quality of life.

Pace, MC, et al. Buprenorphine in long-term control of chronic pain in cancer patients.

Frontiers in Bioscience 2007;(12):1291-1299

Buprenorphine vs Methadone

• Post-partum, maintained on buprenorphine or methadone, 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

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 low intensity 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 high dose 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 (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)