Robin K. Dore, MD. Clinical Professor of Medicine, UCLA. Private Practice Rheumatology, Tustin CA

Transcription

1 Fibromyalgia Robin K. Dore, MD Clinical Professor of Medicine, UCLA Private Practice Rheumatology, Tustin CA Disclosures Clinical Trials: Eli Lilly, Pfizer, Amgen, Abbvie, Novartis, Gilead, Biogen, Sanofi-Genzyme Speakers Bureau: Eli Lilly, Pfizer, Amgen, Abbvie, Novartis, UCB, Celgene, Radius, Sanofi/Genzyme/Regeneron Consultant: Eli Lilly, Pfizer, Amgen, Abbvie, Novartis, Sanofi/Genzyme/Regeneron Objectives Understand the pathophysiology of FM Understand the differential diagnosis, assessment and management Describe pharmacologic and nonpharmacologic management strategies Review the efficacy and safety of therapeutic options for the treatment of FM

2 Definition of Fibromyalgia Chronic widespread pain Fatigue Cognitive dysfunction Sleep deprivation Generalized tenderness Emotional distress Fibromyalgia Definition (cont) Abnormal functioning of the stress response Influenced by genetic and psychologic factors which includes response to every day stress Can occur as primary condition or associated with rheumatic diseases In past, definition included 11/18 tender points but currently it is the constellation of symptoms listed above as the number of tender points does not change with therapy Pathophysiology of FM Neurogenic inflammation is inflammation that is a result of release of various neuropeptides, chemokines and cytokines from peripheral nerve endings in response to tissue damage or painful stimulus It is implicated in many painful conditions such as CRPS, IBS, ICS, migraines Many characteristics of FM results from neurogenic inflammation both in the peripheral and central nervous systems

3 FM: Pathophysiology (cont) Examples include livido reticularis, increased sensitivity to light, touch, smell, sound, taste and increased levels of fibronectin Fibronectin is a tissue marker of endothelial activation Evaluation of the Patient who presents with a diagnosis of fibromyalgia Complete history including childhood and current history of sleep disorders, sexual abuse, stress at home or the workplace Personal and family history of associated conditions such as migraines, IBS, ICS, chronic LBP, CRPS, insomnia, eating disorders Physical examination can reveal cutis marmorata, acrocyanosis, multiple tender points, painful ROM of joints but no joint swelling, no muscle weakness, normal neurological exam and anxiety/depression Laboratory Evaluation of the patient with FM ANA can be positive low titer usually 1:80 or less, speckled pattern Very low ESR common, usually between 0-10 Moderate CK elevations Need to order serologic testing for other autoimmune and auto-inflammatory diseases as FM frequently occurs in patients with underlying rheumatic diseases. Up to 30% of patients with Hashimoto s thyroiditis have FM

4 Goals of Fibromyalgia Management Reduce pain Improve sleep Increase exercise tolerance Improve anxiety/depression associated with pain Improve patient s coping skills with regards to chronic pain management Pain Classification Pain Acute Injury Postoperative flare Chronic Headache (migraine) Neuropathic Diabetic neuropathy Postherpetic neuralgia Radiculopathy Mixed Cancer pain Lower back pain Nociceptive Osteoarthritis Rheumatoid arthritis Fibromyalgia Visceral IBS Pancreatitis Bladder pain Noncardiac chest pain Abdominal pain syndrome Nociceptive vs Neuropathic Pain States Nociceptive Pain Pain that arises from a noxious stimulus Proportionate to the stimulation of the receptor When acute, serves a protective function Can be pathologic when chronic Woolf, Mannion. Lancet. 1999;353:

5 Psychological Effects of Pain Negative emotions Anxiety Depression Sleep deprivation Existential suffering May lead to patients seeking active ending of life Understanding the Mechanisms of Pain How does the nervous system normally process pain? The Pain Pathway Pain Trauma Peripheral nociceptors Activation of the peripheral nervous system Ascending input Spinothalamic tract Peripheral nerve Descending modulation Dorsal horn Dorsal root ganglion Transmission of the pain signal to the brain Activation of CNS at spinal cord

6 Sensitization to Pain 10 Hyperalgesia Pain Intensity Allodynia Injury Normal pain response 2 0 Stimulus Intensity Gottschalk A et al. Am Fam Physician. 2001;63: The Role of Plasticity in Chronic Pain Injury Acute pain Normal healing Healing with plasticity Pain relief Hyperalgesia Allodynia Chronic pain Adapted from Marcus DA. Am Fam Physician. 2000;61: Neuronal Plasticity and Pain Normal adaptive function Neurons detecting and transmitting pain display plasticity A capacity to change function, chemical profile or structure A response to painful stimuli and inflammation A contributor to altered sensitivity to pain When persistent can lead to permanent neuropathic pain Woolf CJ, Salter MW. Science. 2000;288:

7 Choices of Analgesia More Common Acetaminophen NSAIDs Opioids (avoid if possible) Anti-convulsants Central analgesics (tramadol/tapentadol) Less Common Local anesthetics(lidocaine patches 5%) SNRIs Antidepressants *N-methyl D-aspartate Understanding the Mechanisms of Analgesia Review of Analgesic Options What Are the Choices for Providing Analgesia? Most Common Acetaminophen NSAIDs SNRIs Central acting agents (tramadol/tapentadol) *N-methyl D-aspartate Anti-convulsants Less Common Local anesthetics(5% lidocaine patches) Opiates (avoid if at all possible Antidepressants (both TCAs and SSRIs)

8 Acetaminophen Common treatment of mild to moderate pain First-line analgesic therapy for osteoarthritis pain Mechanism of action not fully known, but may involve prostaglandin inhibition in CNS or blockage of peripheral pain impulse generation Available in various combinations with other compounds such as aspirin, caffeine, tramadol, opioids Some evidence suggests that acetaminophen/opioid combinations may cause fewer adverse effects than equianalgesic doses of individual drugs alone Current dosage limits are 3000mg daily What is the Evidence for Acetaminophen? Lack of placebo controlled trials A RDBPCT of diclofenac 75 mg bid vs. APAP 1000 mg qid in 82 subjects with symptomatic OA of the knee 25 patients were randomized to diclofenac, 29 to APAP and 28 to placebo At 2 and 12 weeks, clinically and significant improvements (p<0.001) were seen in the diclofenac treated group; not present in the APAP and placebo treated groups APAP was not significantly different from placebo Case JP et al. Lack of Efficacy of Acetaminophen in Treating Symptomatic Knee Osteoarthritis. Arch Intern Med 2003;163: Acetaminophen Toxicity Reduce dose in the elderly Beware of toxicity from use of multiple acetaminophencontaining products Alcohol users and abusers Warfarin interaction: Anticoagulant effect is potentiated in a dose-response fashion INR levels should be monitored in patients taking warfarin who require sustained acetaminophen

9 NSAIDs and Coxibs Use in FM for analgesia as role of inflammation in FM is still being evaluated If no response to one, may respond to another Lower doses are analgesic, higher doses anti-inflammatory Side effects include: GI: Gastroprotection increases expense; misoprostol compliance problematic; PPI use can be associated with other adverse events eg interaction with clopidogrel and increased risk of hip fracture Renal: Edema, HTN, rarely causes CHF, but exacerbates CHF; impaired function, rarely, acute renal failure Platelets: Antiplatelet effects (however, use of aspirin with ibuprofen blocks CV-protective effects of aspirin) CV: Increased risk of MI, stroke, arrhythmia (class label) Drawbacks of NSAIDs Gastrointestinal Renal Cardiovascular Peptic ulceration; gastrointestinal hemorrhages Esophagitis and strictures Small and large bowel erosive disease Reversible acute renal failure Fluid and electrolyte disturbance Chronic renal failure Interstitial nephritis Nephrotic syndrome Exacerbation of hypertension, congestive heart failure, angina Decreased platelet aggregation (except celecoxib Increased CV risk, including MI, stroke and arrythmia Brooks P. Am J Med. 1999;10(Suppl) 3A:9S-13S. Carver AC, et al. Neurol Clin. 2001;19: Moreland LW, et al. Rheum Dis Clin North Am. 1999;25: Gloth FM III. Clin Geriatr Med. 2001;17: FDA NSAID Class Label Risk Factors for Serious GI Complications from NSAIDs Advanced age Disability Higher NSAID dosages H. pylori History of GI problems Concomitant corticosteroids Concomitant anticoagulants, e.g., aspirin or warfarin Rheumatoid arthritis See, Lanas A et al. Nitrovasodilators, Low-Dose Aspirin, Other Nonsteroidal Antiinflammatory Drugs, and the Risk of Upper Gastrointestinal Bleeding. N Engl J Med 2000;343:

10 Nonopioid Analgesics Tramadol Titrate dose up; lower dose in elderly Affects opioid, serotonin and norepinephrine pathways Non-ulcerogenic: Not an NSAID May be added to NSAIDs, acetaminophen and narcotic analgesics Side effects: Nausea, vomiting, lowered seizure threshold, constipation, drowsiness, dizziness Not to be used in patients on TCAs or a history of substance abuse/dependence Medical Letter. 1999;41: Tapentadol Combines opioid and non-opioid activity in one centrally acting oral analgesic. Works primarily on ascending pathways to inhibit transmission of pain impulses through binding to mu-opioid receptors Norepinephrine reuptake inhibitor works primarily on the descending pathways to enhance the inhibition of pain signaling Most common adverse events are nausea, dizziness, vomiting, somnolence and headache Dosing is 50, 75 or 100mg every 4-6 hours with max dose of 600mg per day Opiates no better than NSAIDs for chronic back or arthritis pain Krebs et al (JAMA, 2018;319(9): ) randomly assigned 240 patients seeking pain treatment at the VA to receive either opioids, acetaminophen or ibuprofen for one year 65% of patients had back pain and the rest hip or knee osteoarthritis pain Patients in the opioid group started with a fast-acting morphine, hydrocodone-apap or oxycodone IR and advanced to LA morphine or oxycodone and then fentanyl patches if needed

11 Krebs et al (continued) In the non-opioid group, patients started with acetaminophen and NSAIDs then added gabapentin and lidocaine patches followed by pregabalin and tramadol In both groups, the initial pain score was 5.4 on a 10 point Likert scale but decreased to 4.0 with opiates and 3.5 in the non-opiate group No one in the opiate group developed signs of opioid misuse, abuse or addiction and did not develop opioid-induced hyperalgesia CDC Guideline for Prescribing Opioids for Chronic Pain Non-pharmacologic and nonopioid pharmacologic therapy are preferred Opioids should only be considered if expected benefits for both pain and function are anticipated to outweigh risks to the patient If opioids are used, they should be combined with non-pharmacologic therapy and nonopioid therapy as appropriate CDC Guideline (continued) Before starting opioid therapy for chronic pain, treatment goals should be discussed including realistic goals for pain and function Consider stopping opioids if there is no clinically meaningful improvement in pain and function Periodically during opioid therapy, discuss known risks and realistic benefits and the patient and clinician responsibilities for managing therapy

12 CDC Guideline (continued) When starting opioids, use IR opioids at the lowest effective dose Reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents(mme) or more and avoid increasing dosage to 90 MME/day or carefully justify a decision to titrate up to this dose Since long-term opioid use often begins with acute pain, use the lowest effective dose of IR opioids, 3 days or less will often be sufficient and more than 7 days is rarely needed CDC Guideline (continue) Clinicians should re-evaluate benefits and harms within 1-4 weeks of starting opioid therapy for chronic pain or dose escalation Patients should be re-evaluated every 3 months or more frequently for the need of continued therapy Before starting and periodically during therapy, clinicians should evaluate risk factors for opioidrelated harms Clinicians should review state PDMP data CDC Guidelines (continued) When prescribing opioids for chronic pain, clinicians should use urine drug testing before starting and at least annually during therapy Clinicians should avoid prescribing opioids and benzodiazepines concurrently whenever possible Clinicians should arrange for methadone or buprenorphine in combination with behavioral therapies for patients with opioid use disorder

13 Drawbacks of Opioid Analgesics Limitations Special Issues Respiratory depression Constipation, nausea, and vomiting Sedation and cognitive impairment Histamine release (urticaria, sweating, vasodilation, pruritus) Urinary retention Drug-to-drug interactions Physical dependence and tolerance with chronic use No data that they are effective in fibromyalgia pain Withdrawal syndrome with abrupt cessation Short-acting single and combination opioid agents require multiple daily doses Costs associated with adverse events Moreland LW, et al. Rheum Dis Clin North Am. 1999;25: Power I, et al. Surg Clin North Am. 1999;79: Miyoshi HR. Bonica s Management of Pain. 2001: Anticonvulsants Carbamazepine Indicated for trigeminal neuralgia; diabetic neuropathy Lamotrigine Indicated for trigeminal neuralgia, HIV and central pain Gabapentin Indicated for diabetic neuropathy and postherpetic neuralgia Topiramate Pramipexole Zonisamide Pregabalin-indicated for FM, DPNP, PHN Backonja. Neurology. 2002;59:S14-S17. is xk7vyq0a Serotonin-norepinephrine re-uptake inhibitors Duloxetine approved for the treatment of depression, fibromyalgia, back pain and OA with dosage ranges from mg daily Milnacipran approved for pain of fibromyalgia with dosage ranges from mg daily Common adverse reactions include agitation, insomnia, tremors, nausea, headache, sweats Care must be given when used in combination with tramadol to avoid serotonin syndrome

14 Gabapentinoids Gabapentinoid use in the US increased from 1.2% in 2002 up to 3.9% in 2015 This is partly explained by the CDC guidelines to use gabapentinoids to reduce dependence on opiates In 2016, over 64 million prescriptions were written for gabapentin in the US Pregabalin is already scheduled and gabapentin is starting to be scheduled in several states Gabapentinoids (continued) CW Goodman and AS Brett in the NEJM 2017 wrote We suspect that clinicians who are desperate for alternatives to opiates have lowered their threshold for prescribing gabapentinoids to patients with various types of acute, sub-acute and non-cancer pain In Addiction Medicine, experts state that addicts are using gabapentinoids to boost the euphoric effects of opiates Analgesic MoA Differ Among Available Pain Medications Agent Acetaminophen Tramadol Mechanism of Action Decreases pain and possibly fever through inhibition of COX-3 1 Mixed actions opioid agonist plus norepinephrine/serotonin reuptake inhibitor Opioids NSAIDs tapentadol Anticonvulsants (eg, gabapentin/pregabalin) Chandrasekharan NV et al. Proc Natl Acad Sci USA. 2002;99: Ashton H, Young MH. J Psychopharmacol. 2003;17: Bind to opioid receptors, producing agonist action that inhibits pain impulses Inhibition of COX-1 and COX-2 isoenzymes inhibits prostaglandin synthesis Mixed actions-binds to mu-opiate receptor and inhibits norepinephrine re-uptake Sodium and calcium channels

15 Multimodal Analgesia Opioids NSAIDs, COX-2, acetaminophen, nerve blocks Potentiation Reduced doses of each analgesic Improved pain relief due to synergistic / additive effects May reduce severity of side effects of each drug Kehlet H, Dahl JB. Anesth Analg. 1993;77: Synergistic or Additive Effects of Analgesic Combinations Decreasing Opioid Use Additive or synergistic analgesia can provide better pain control Lower doses of individual agents may be used Opioid sparing Opioid Alone Multimodal Approach Agency for Health Care Policy and Research (AHCPR) AHCPR Publication No AHCPR 1992; AHCPR Publication No ; Kehlet H et al. Anesth Analg. 1993;77: Challenges of Polypharmacy Patient convenience and compliance Drug interactions Increased risk factor for the elderly Shakib S. Aust Fam Physician. 2002;31:

16 Pain Management Guidelines Analgesic drug therapy is the mainstay of treatment Treatment should be individualized to the needs of the patient and titrated to provide effective analgesia Drug therapy is part of a multimodal approach American Pain Society (APS) Agency for Healthcare Research Quality (AHRQ), World Health Organization (WHO) Carver AC et al. Neurol Clin. 2001;19: Multimodal Analgesia: Agents Combinations of varying agents Local anesthetics(lidocaine patches 5%) available OTC as Salon-pas or Icy Hot with 4% Lidocaine Opiates (try to avoid in FM patients) Tramadol/tapentadol NSAIDs Acetaminophen Anti-convulsants Multimodal Approach to Pain Management Nondrug Therapy: Drug Therapy: PT, biofeedback, NSAIDs, non-opioids, acupuncture, etc opioids, antidepressants,anti-convulsants Injection Therapy,

17 Nonpharmacologic Management of Pain Moist heat or dry cold, varies among patients Electrical nerve stimulation (TENS or MENS, acupuncture Relaxation techniques, biofeedback, hypnosis, cognitive behavioral therapy, massage therapy, myofascial release Physical /Occupational therapy/exercise Mental health counseling/stress reduction Proper sleep hygiene Non-pharmacologic therapies without proven benefit Hyperbaric oxygen chamber treatments Alkaline water Infrared light treatments Cold shock therapy Infusions of vitamins and minerals Breathing high concentrations of oxygen Role of Acupuncture in Pain Suppresses substance P Imposes pre-/postsynaptic inhibitory control ß-endorphin released from the arcuate nucleus ACTH released from the pituitary gland Serotonin, norepinephrine, GABA, dopamine modulation have been identified

18 Injection Therapy Trigger point injections may contain local anesthetic such as lidocaine or marcaine plus or minus steroids If contain steroids, limit use to every three months and no more than 3 injections at a time If only contain local anesthetic can be given more often Some practitioners use injections of NS, but very little date with regards to efficacy Principles of Managing Pain Chronic pain is not just persistence of acute pain The neurophysiological basis of pain is multimodal, with both peripheral and central components Patients may exhibit more than one mechanism of pain generation eg, an autoimmune disease plus FM Even if the autoimmune disease is in remission, the symptoms of FM can continue Effective management of fibromyalgia demands a willingness of all parties (patient, loved ones, providers) to be able to accept the diagnosis, work together to improve quality of life, not be judgemental Often requires collaboration with a mental health professional to help accept limitations that disease causes Conclusions Under-treated FM significantly impacts the patient s quality of life and increases health care costs Must consider` pharmacologic and non-pharmacologic options Pharmacotherapy should always take into account Long-term effects Comorbidities Drug-drug interactions Compliance Fibromyalgia is a real disease as demonstrated by fmri Treat, monitor, and reassess frequently If the patients symptoms worsen, consider a new life stressor may have occurred or the patient could have developed another rheumatic disease