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11/2/2011 Chronic Pain in the Patient with Mental Health Issues Neil B. Sandson, M.D. Psychiatrist, Veterans Affairs Maryland Health Care System Director, Psychopharmacology Consultation Service; Sheppard Pratt Health System Clinical Associate Professor, University of Maryland Medical School, Department of Psychiatry Core Concepts Understand the physiologic causes and types of chronic pain. Identify mental health issues that may produce and/or aggravate chronic pain. Elucidate the interplay between mental illness issues and physiologic issues in the expression and experience of chronic pain. 1 11/2/2011 Core Concepts Craft a comprehensive treatment plan that addresses all physiologic and mental health dimensions of the ppatient’s condition Multidisciplinary and concurrent, when possible Communication and collegiality Monitor adherence Chronic Pain - Classifications General Somatic Pain Visceral Pain Bone Pain Muscle Spasm Peripheral Neuropathy Vasculopathy Vasculopathy--Induced Headaches Chronic Pain - Classifications General Somatic Pain Skin/muscle injury or other pathology Includes fibromyalgia 2 11/2/2011 Chronic Pain - Classifications Visceral Pain Pain arising from pathology involving internal organs Chronic pancreatitis Chronic cholelithiasis Chronic active hepatitis Chronic Pain - Classifications Bone Pain Arthritis Osteomyelitis Osteoporosis Bone Cancer Chronic Pain - Classifications Muscle Spasms Often involved in chronic back pain Quite variable with activity 3 11/2/2011 Chronic Pain - Classifications Peripheral Neuropathy Radiculopathies, like sciatica Herpetic neuralgia Diabetes Diabetes--induced Chronic Pain - Classifications Vasculopathy-Induced Vasculopathy Basically chronic ischemic pain Diabetes Tobacco use Autoimmune diseases Claudication Claudication--induced Reflex Sympathetic Dystrophy Chronic Pain - Classifications Headaches Migraine Tension Sinus Cluster 4 11/2/2011 Mental Health Issues Depression Anxiety Psychosis Drug/Alcohol Abuse Mental Health Issues Depression Dysphoria Anhedonia Increased/decreased sleep Weight/appetite change Anergia Psychomotor changes Poor concentration Guilt Suicidality Mental Health Issues Depression The PHQPHQ-9 is a quick and easy assessment tool ideally suited to primary care settings. www.agencymeddirectors.wa.gov/Files /depressoverview.pdf 5 11/2/2011 Mental Health Issues Depression Can markedly increase sensitivity to pain and decrease ability to tolerate discomfort. Of course, undertreated chronic pain can produce or exacerbate depression. Mental Health Issues Anxiety Generalized Anxiety Disorder Panic Disorder with or without agoraphobia PTSD Obsessive Compulsive Disorder Others Mental Health Issues Anxiety As with depression, anxiety symptoms can undermine the patients ability to participate in and/or benefit from treatment of chronic pain, but undertreated pain can also produce or greatly worsen anxiety symptoms. 6 11/2/2011 Mental Health Issues Psychosis Delusions Hallucinations Thought Disorder Bizarre behaviors Mental Health Issues Psychosis For obvious reasons, active psychotic symptoms can undermine the patient patient’ss ability to participate in and comply with treatment of chronic pain Undertreated pain can exacerbate psychosis, particularly paranoia, and associated impulsivity. Mental Health Issues Drug/Alcohol Abuse Alcohol/other sedativesedative-hypnotics (BZDs) Cocaine/stimulants Cannabis Opioids PCP/ketamine/hallucinagens 7 11/2/2011 Mental Health Issues Drug/Alcohol Abuse This poses perhaps the greatest challenge to patients and clinicians alike, because more than any other psychiatric comorbidity, sequalae of these illnesses often undermine the trust at the heart of a healthy and productive doctor doctor--patient relationship. Mental Health Issues Patients Will he/she really listen to and believe me? Can I be honest with my doctor? If I am, might he/she restrict my treatment options? Clinicians Is my patient being honest with me? Can I trust them to adhere to treatment and not misuse and/or divert the medications that I am providing to them? Mental Health Issues Drug/Alcohol Abuse Pseudoaddiction: A drugdrug-seeking behavior that simulates true addiction, which occurs in patients with pain who are receiving inadequate pain medication. 8 11/2/2011 Treatment Physiologic PCP Appropriate pp p specialists p ((neurology, gy orthopedics, p pain service, etc.) Mental Health Medication management (psychiatrist or NP) with appropriate psychotherapies and psychosocial supports Treatment Multidisciplinary Approach Shared/Group Clinics or defined Pain Service Open lines of communications Clearly defined roles/responsibilities – Who does what? Case conferences Specific Topics: Drug-Drug Interactions A DDI occurs when one drug exerts an influence upon the action of another drug. Pharmacodynamic Pharmacodynamic:: one drug’s alteration of another drug drug’ss action at its intended site of action (eg: MAOI with SSRI leads to serotonin syndrome) Pharmacokinetic Pharmacokinetic:: one drug’s alteration of another drug’s movement through the body, often resulting in changes in blood levels (fluoxetine added to NTP raises NTP levels). 9 11/2/2011 Specific Topics: Drug-Drug Interactions Cytochrome P450 System: A family of enzymes (usually hepatic) which performs oxidative metabolism on a broad array y of substances (substrates). “Number “Number--letter letter--number” sequence identifies enzyme in a manner analogous to “family“family-genus genus--species” for animals. Specific Topics: Drug-Drug Interactions Substrate: An agent that is metabolized by Substrate: an enzyme into a metabolic end product and eventuallyy excreted. Specific Topics: Drug-Drug Interactions Inhibitor:: An agent which interferes with the Inhibitor ability of a given enzyme to metabolize a given substrate. This is usually competitive (by a coco-substrate) rather than nonnon-competitive (impairs enzyme functioning). The introduction of inhibitors generally leads to rapid increases in the blood levels of substrates. 10 11/2/2011 Specific Topics: Drug-Drug Interactions Inducer:: An agent which causes an increase Inducer in the production of the enzyme(s) responsible p for metabolizingg a ggiven substrate. The introduction of inducers generally leads to gradual (1 to 3 weeks) decreases in the blood levels of substrates. Specific Topics: Drug-Drug Interactions Coadministration of substrates and inhibitors of the same enzyme leads to increases in substrate blood levels levels. Coadministration of substrates and inducers of the same enzyme leads to decreases in substrate blood levels. Specific Topics: Drug-Drug Interactions Metabolic variability Poor metabolizers (PMs): blood levels of substrates are higher than expected at standard doses. genetic polymorphisms acquired PM status through the addition of an inhibitor 11 11/2/2011 Specific Topics: Drug-Drug Interactions Metabolic variability Extensive (rapid) metabolizers – normal significant variability even within the bounds of “normal” – 10 10--30 30--fold variations in efficiency of 3A4 function without polymorphisms Specific Topics: Drug-Drug Interactions Metabolic variability Ultraextensive/ultrarapid metabolizers (UEMs): blood levels of substrates are lower than expected at standard doses. extra allelic copies of the wildwild-type enzyme Specific Topics: Drug-Drug Interactions Phase II metabolism: Also referred to as glucuronidation, this is the “capstone” to phase I (P450) metabolism. It increases the hydrophilicity off metabolites t b lit andd thus th makes k them th more readily dil excretable. There are substrates, inhibitors, and inducers, just like P450. “UGT” is the main phase II enzyme system 12 11/2/2011 Specific Topics: Drug-Drug Interactions Nonnarcotic analgesics Cyclooxygenase Cyclooxygenase--2 (COX(COX-2) Inhibitors Aspirin Acetaminophen Nonsteroidal Anti Anti--Inflammatory Drugs (NSAIDs (NSAIDs)) Narcotic analgesics Phenylpiperidines Morphine and related compounds Methadone, Propoxyphene, Propoxyphene, and Tramadol Nonnarcotic Analgesics COX-2 Inhibitors COX Celecoxib (Celebrex) Metabolized by: 2C9 2C9, unspecified UGTs Inhibits: 2D6 Induces: None Nonnarcotic Analgesics COX-2 Inhibitors COX Diclofenac (Voltaren) Metabolized by: 2C9, 3A4, UGT 1A9, UGT 2B7 (to (t hepatotoxic h t t i metabolite) t b lit ) Inhibits: UGT 2B7 Induces: None DDI issues: PMs for 2C9 or coadministration of 2C9 inhibitors increases hepatotoxicity via increased use of UGT 2B7 pathway. 13 11/2/2011 Nonnarcotic Analgesics COX-2 Inhibitors COX Etodolac (Lodine) Metabolized by: 2C9 2C9, UGT 1A9 Inhibits: 2C9 (weak) Induces: None Nonnarcotic Analgesics COX-2 Inhibitors COX Meloxicam (Mobic) Metabolized by: 2C9 2C9, 3A4 Inhibits: 2C9, 3A4 Induces: None Nonnarcotic Analgesics COX-2 Inhibitors COX Nabumetone (Relafen) Pro Pro--drug Metabolized by: unspecified phase I enzyme and unspecified UGTs Inhibits: None Induces: None 14 11/2/2011 Nonnarcotic Analgesics Aspirin Pro Pro--drug Metabolized by: y deacetylation y to salicylic y acid, which is then metabolized by UGT 2B7 and other UGTs, as well as glycine conjugation Inhibits: UGT 2B7, betabeta-oxidation, possibly other UGTS (all via salicylic acid) Induces: None Nonnarcotic Analgesics Aspirin DDI issues: Coadministration (at least 325 mg/day) with VPA can increase free VPA levels more than 44-fold. Nonnarcotic Analgesics Acetaminophen Metabolized by: UGTs 1A1, 1A6, 1A9, 2B15; sulfation; 2E1, 3A4, and 1A2 Inhibits: None Induces: None 15 11/2/2011 Nonnarcotic Analgesics NSAIDs Diflunisal (Dolobid) Fenoprofen p (Nalfon) ( ) Flurbiprofen (Ansaid) Ibuprofen (Advil, Motrin) Indomethacin (Indocin) Ketoprofen (Actron, Orudis) Ketorolac (Toradol) Nonnarcotic Analgesics NSAIDs (cont) Meclofenamate (Meclomen) Mefenamic Acid ( (Ponstel)) Naproxen (Aleve, Naprosyn) Oxaprozin (Daypro) Piroxicam (Feldene) Sulindac (Clinoril) Tolmentin (Tolectin) Nonnarcotic Analgesics NSAIDs Metabolized by: Generally 2C9 • Except for: tolmentin (3A4), diflunisal, fenoprofen, and sulindac Generally UGT 2B7 Inhibits: Generally UGT 2B7 Except for: flurbiprofen, ketorolac. oxaprozin, piroxicam, and tolmentin, none of which inhibits any enzymes Induces: None 16 11/2/2011 Nonnarcotic Analgesics NSAIDs DDI issues All 2C9 inhibiting NSAIDs can raise free PHT levels. All NSAIDs, except for aspirin and sulindac, can raise lithium levels (20% to 200%). Narcotic Analgesics Phenylpiperidines Fentanyl (Duragesic) Meperidone (Demerol) Narcotic Analgesics Fentanyl Metabolized by: 3A4 Inhibits: 3A4 Induces: None 17 11/2/2011 Narcotic Analgesics Meperedine Metabolized by: 2B6, 3A4, 2C19, possibly some UGTs Inhibits: I hibit None N Induces: None DDI issues: Coadministration of 3A4 inducers can lead to increased production of the longlonglived, neurotoxic, normeperidine metabolite. There are known cases with chronic ritonavir and phenobarbital. Narcotic Analgesics Morphine and related compounds Buprenorphine (Buprenex) Codeine Hydrocodone (Vicodin - with acetaminophen) Hydromorphone (Dilaudid) Morphine Oxycodone (Oxycontin) Narcotic Analgesics Buprenorphine Metabolized by: 3A4, UGT 2B7, UGT 1A3 Inhibits: None Induces: None DDI issues: When coadministered with narcotic analgesics, it is likely to displace them from mu receptors and reduce analgesic efficacy. 18 11/2/2011 Narcotic Analgesics Codeine Pro Pro--drug Metabolized by: 2D6 (into morphine), 3A4, UGT 2B7 (80%) Inhibits: UGT 2B7 Induces: None DDI issues: Coadministration with 2D6 inhibitors, or 2D6 PM status, is likely to impair the conversion to morphine and reduce analgesic efficacy. Narcotic Analgesics Hydrocodone Pro Pro--drug Metabolized by: 2D6 (into hydromorphone), 3A4 Inhibits: None Induces: None DDI issues: Coadministration with 2D6 inhibitors, or 2D6 PM status, is likely to impair the conversion to hydromorphone and reduce analgesic efficacy. Narcotic Analgesics Hydromorphone Metabolized by: 2D6, 3A4, UGT 1A3, UGT 2B7, possibly other UGTs Inhibits: None Induces: None 19 11/2/2011 Narcotic Analgesics Morphine Metabolized by: UGT 2B7, UGT 1A3, slightly by 3A4 and 2D6 Inhibits: UGT 2B7 Induces: None Narcotic Analgesics Morphine DDI issues: UGT 2B7 converts morphine into morphine--6-glucuronide (M6G), which is, in morphine vitro, 50 times more potent as a mu agonist than parent morphine. It is theoretically possible, but as yet not demonstrated, that coadministration of UGT 2B7 inhibitors (such as most NSAIDs) could impair morphine’s analgesic efficacy. Narcotic Analgesics Oxycodone Metabolized by: 2D6, 3A4, metabolites then by UGT 2B7 Inhibits: None Induces: None 20 11/2/2011 Narcotic Analgesics Methadone Metabolized by: 3A4, 2B6, 2D6 (minor) Inhibits: 2D6, 3A4, UGT 2B7 Induces: None DDI issues Beware coadministration with inhibitors or inducers of 3A4 (or 2B6). Beware coadministration with other QT prolongers. Narcotic Analgesics Tramadol Pro Pro--drug Metabolized by: 2D6 (into M1) M1), 3A4, 3A4 2B6, unspecified UGTs Inhibits: None Induces: None Narcotic Analgesics Tramadol DDI issues Coadministration with 2D6 inhibitors, or 2D6 PM status, t t iis lik likely l to t impair i i the th conversion to M1 and reduce analgesic efficacy, as well as further lower the seizure threshold. Coadministration with other serotonergic agents may predispose to serotonin syndrome, but this is not overwhelmingly likely. 21 11/2/2011 Other Analgesic Agents Gabapentin (Neurontin) Duloxetine (Cymbalta) Venlafaxine (Effexor) TCAs Pregabalin (Lyrica) Other Analgesic Agents Gabapentin Metabolized by: None -- purely renally excreted Inhibits: None Induces: None Other Analgesic Agents Duloxetine Metabolized by: 1A2, 2D6 Inhibits: 2D6 Induces: None 22 11/2/2011 Other Analgesic Agents Venlafaxine Metabolized by: 2D6 (major), 3A4 and 2C19 (minor) Inhibits: 2D6 (weak) Induces: None Other Analgesic Agents TCAs Metabolized by: 2D6 (all); 2C19, 3A4, and 1A2 (tertiary amines) Inhibits: I hibit 2D6 ((mild ild to t moderate), d t ) mild ild inhibition of assorted P450s depending on which specific TCA is considered Induces: None DDI issues: low therapeutic index, caution with 2D6 and other inhibitors. Other Analgesic Agents Pregabalin Metabolized by: very little – mostly excreted unchanged Inhibits: none Induces: none 23 11/2/2011 Meet the Enzymes 3A4 2D6 1A2 2C9 2C19 2E1 2B6 3A4 Notable substrates alprazolam carbamazepine calcium channel blockers clopidogrel cyclosporin/tacrolimus ethinylestradiol/progesterone several “statins” – atorvastatin, lovastatin, and simvastatin steroid compounds tertiary amine TCAs (IMI, AMI, etc.) zolpidem/zaleplon 3A4 Notable inhibitors azole antifungals cimetidine ciprofloxacin/norfloxacin diltiazem/verapamil fluoxetine/fluvoxamine grapefruit juice HIV protease inhibitors macrolide antibiotics (except azithromycin) nefazodone 24 11/2/2011 3A4 Notable inducers barbiturates carbamazepine modafinil oxcarbazepine (for ethinyl estradiol only) phenytoin rifampin ritonavir St. John’s wort topiramate 2D6 Notable substrates ß-blockers codeine → morphine p hydrocodone → hydromorphone risperidone → 9-OH risperidone (paliperidone) tamoxifen → 4-hydroxytamoxifen (endoxifen) TCAs tramadol → M1 2D6 Notable inhibitors bupropion cimetidine duloxetine fluoxetine paroxetine quinidine ritonavir sertraline (>150 mg/d) 25 11/2/2011 2D6 No known inducers 1A2 Notable substrates caffeine (and other xanthines, like theophylline) clozapine cyclobenzaprine olanzapine 1A2 Notable inhibitors caffeine cimetidine ethinylestradiol fluoroquinolones fluvoxamine grapefruit juice ticlopidine zafirlukast 26 11/2/2011 1A2 Notable inducers large amounts of cruciferous vegetables (broccoli, brussel sprouts, cauliflower, etc.) or charchar-grilled meats carbamazepine rifampin tobacco smoking 2C9 Notable substrates glipizide/glyburide phenytoin S-warfarin 2C9 Notable inhibitors cimetidine clopidogrel fluconazole fluoxetine/fluvoxamine metronidazole ritonavir sulfamethoxazole valproate zafirlukast 27 11/2/2011 2C9 Notable inducers carbamazepine phenobarbital phenytoin rifampin 2C19 Notable substrates diazepam phenytoin tertiary amine TCAs 2C19 Notable inhibitors cimetidine disulfiram ethinylestradiol fluoxetine fluvoxamine modafinil omeprazole ritonavir topiramate 28 11/2/2011 2C19 Notable inducers (same as 2C9) carbamazepine phenobarbital phenytoin rifampin 2E1 Notable substrates acetaminophen ethanol 2E1 Notable inhibitors disulfiram isoniazid watercress 29 11/2/2011 2E1 Notable inducers chronic ethanol use (leads to increased hepatotoxicity following acetaminophen OD due to increased production of NAPQI). isoniazid obesity retinoids tobacco smoking 2B6 Notable substrates bupropion cyclophosphamide/ifosfamide tamoxifen 2B6 Notable inhibitors fluoxetine fluvoxamine nefazodone paroxetine sertraline 30 11/2/2011 2B6 Notable inducers phenobarbital phenytoin rifampin Phase II Metabolism Notable substrates lamotrigine olanzapine several NSAIDs morphine codeine bilirubin AZT valproate Phase II Metabolism Notable Inhibitors valproate probenecid sertraline milk thistle significant competitive inhibition with other substrates 31 11/2/2011 Phase II Metabolism Notable Inducers phenobarbital carbamazepine phenytoin ethinylestradiol oxcarbazepine rifampin Case Vignettes Sad and Sore More Bang for the Buck The Tremulous Triathlete Gradual Withdrawal Case Vignettes Sad and Sore Fluoxetine was added to hydrocodone. 2D6 was inhibited. Hydrocodone was not able to be metabolized into hydromorphone. Loss of analgesia resulted. Analgesia returned with removal of fluoxetine. 32 11/2/2011 Case Vignettes More Bang for the Buck A patient was given small doses of codeine for a cough due to bilateral pneumonia, soon after which the patient developed lifelife-threatening opioid intoxication. Genotyping revealed 3 or more functional alleles for 2D6 (UM phenotype). Codeine → morphine via 2D6 Codeine + 2D6 UM phenotype can yield increases in morphine levels up to 800%! Case Vignettes The Tremulous Triathlete Indomethacin was added to lithium. Inhibition of p prostaglandin g synthesis y interfered with the excretion of lithium. The lithium level increased significantly (about 50% in this case), resulting in polyuria, feeling “spacey”, and tremor. 33 11/2/2011 Case Vignettes Gradual Withdrawal Carbamazepine was added to chronic methadone. 3A4 was induced. i d d The blood level of methadone decreased significantly (by about 60%). Opioid withdrawal resulted. This could also have occurred if PHT or phenobarbital was added to methadone. Specific Topics – Comorbid Chronic Pain and Drugs/Alcohol The most vexing issue is whether, and under what conditions, to administer narcotic analgesics g to ppatients with comorbid drug/alcohol abuse. Specific Topics – Comorbid Chronic Pain and Drugs/Alcohol What are the problems? Abuse Diversion Overdose suicide inadvertent Interactions with drugs and alcohol CNS depression, arrhythmias, etc. 34 11/2/2011 Specific Topics – Comorbid Chronic Pain and Drugs/Alcohol Prudent Measures When possible, obtain objective evidence of physiologic derangements that would justify administration of narcotic analgesics. Treatment “contracts” Critical component: Patient will report inadequate tx of pain, anxiety, etc., rather than unilaterally pursue “self“self-treatment” Drug/alcohol screens – frequent and random Specific Topics – Comorbid Chronic Pain and Drugs/Alcohol Warning Signs Premature refills Loss/destruction of meds Excessive somnolence Marked changes in manifest symptoms when pt is unaware of being observed vs. aware of such observation, protean symptoms, etc. Specific Topics – Comorbid Chronic Pain and Drugs/Alcohol What to do if “irregularities” emerge Explore concerns with the patient Check area pharmacy records Increase intensity of monitoring If safety issues are too compelling or if clear abuse/diversion is occurring, then taper and discontinue narcotic analgesics. 35 11/2/2011 Specific Topics – Comorbid Chronic Pain and Drugs/Alcohol Key consideration If we underunder-treat the pain and anxiety of our patients, we make it quite difficult for them to comply with our treatment contracts. Therefore, if/when irregularities emerge, we need to ask ourselves the question, are these irregularities potentially attributable to such under--treatment? under Specific Topics – Comorbid Chronic Pain and Drugs/Alcohol Corollary Ethical Consideration All other things being equal, as clinicians, what is our more compelling ethical imperative? To minimize underunder-treatment, even if we thus run a greater risk of allowing abuse and diversion to occur, OR To minimize the risk of abuse and diversion, even if we thus run a greater risk of underundertreating our patients. DDI References Clinical Manual of Drug Interaction Principles for Medical Practice, by Gary Wynn, y M.D., Jessica Oesterheld, M.D., Kelly Cozza, M.D., and Scott Armstrong, M.D. 36 11/2/2011 DDI References Drug-Drug Interaction Primer: A Compendium of DrugCase Vignettes for the Practicing Clinician, by Neil Sandson, M.D. Dr. Oesterheld’s site is at: http://www.mhc.com/Cytochromes DDI program is at www.genelex.com Pub med is at: http://www.ncbi.nlm.nih.gov/pubmed DDI References Dr. Flockhart’s site is at: www.drug www.drug-interactions.com (hyperlinks to pub med) The Physicians’ y Desk Reference online is at: www.pdr.net Existing drug interaction programs (ePocrates, ePocrates RxPro, MICROMEDEX, etc.) are not great (in my humble opinion), but they are a good deal better than nothing. Take-home message Calculated risks of abuse are taken in order to preserve higher values. Warren E. Burger 37