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

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 Dependence vs Addiction

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). Opioid Use in a Household Survey Population 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):

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 well- being without full opioid effects Very slow dissociation rate  prolonged therapeutic effects. Ceiling effect

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.

Kosten T and O'Connor P. N Engl J Med 2003;348: Severity of Opioid-Withdrawal Symptoms after Abrupt Discontinuation of Equivalent Doses of Heroin, Buprenorphine, and Methadone

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:

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

 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 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):

Chronic Cancer Pain Transdermal buprenorphine vs. sustained- release 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):

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:

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

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;

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):

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):

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.

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 (For DATA training)