Pain Management

  • NSAIDs
  • Salicylates
    • Aspirin (ASA)
    • Slows the bd of oral hypoglycemics (decrease hypoglycemic dose)
    • Monitor when used with Lithium

  • Acetic Acid Derivatives

    • Blocks COX1 and COX2
    • Bromfenac (Prolensa, Bromday)
    • Diclofenac (Voltaren)
    • Indomethacin
    • Ketorolac (Toradol)
    • Oxicams
    • Meloxicam (Mobic)
    • Piroxicam (Feldene)
    • Propionic Acid Derivatives
    • Ibuprofen
    • SE: Hyperkalemia, Hyponatremia, Hypokalemia + RTA (hyperchloremic metabolic acidosis, low urine anion gap)
    • Naproxen
    • Coxibs
    • Celecoxib (Celebrex)
    • COX1 completely, COX2 some
    • Etodolac
    • COX1 completely, COX2 some
    • Parecoxib (Dynastat)
    • Other
    • Nabumetone (Relafen, Relifex)
    • Neuropathic Pain
    • Orders of loss:
    • 1) Pain
    • 2) Temperature
    • 3) Touch
    • 4) Pressure
    • TCAs (Amitriptyline/Nortriptyline)
    • Decrease reuptake of serotonin and norepinephrine
    • Inhibition of pain signals
    • Can be used in patients with Depression + Neuropathy
    • CI: ≥65, pre-existing Cardiac disease
    • Anticonvulsants
    • Gabapentin Enacarbil (Horizant)
    • Not FDA approved
    • Influence synthesis/uptake of GABA
      • Does not Bind GABA-A/GABA-B
    • Restless leg, neuropathy, anxiety
    • Gabapentin (Neurotin)
    • Not FDA approved
    • Antiepileptic, migraine prevention, diabetic neuropathy, RLS
    • Pregabalin (Lyrica)
    • Dose: 50mg BID to TID
    • MOA: Decreased depolarization of neurons in CNS
      • Inhibits the release of excitatory neurotransmitters by binding voltage gated calcium modulators on nerve endings
      • 6x binding affinity of gabapentin
      • May potentiate opioids/benzos
    • Use: FDA for fibromyalgia
    • SE: drowsiness, weight gain, fluid retention
    • Dual SNRIs (Duloxetine)
    • In painful diabetic neuropathy
    • Opioids (Oxycodone)
    • Activation of central opioid receptors
    • Capsaicin (Topical)
    • Loss of membrane potential in nociceptive fibers
    • Lidocaine (Topical)
    • Decreased depolarization of neurons in peripheral nerves
    • Milnacipran (Savella)
    • SNRI
    • Medical Cannabis
    • Some efficacy in the treatment of chronic non-cancer pain
    • Chronic inflammatory Demyelinating neuropathy
    • Distal paresthesias and numbness
    • Motor weakness in upper and lower extremities
    • Somatic Pain
    • Joint pain
    • NSAIDs (Ketorolac)
    • DMARDs
    • Pts on prednisone ≥20mg/day, methotrexate ≥25mg/week, and azathioprine ≥3mg/kg/day should avoid live vaccines
    • Nonbiologic agents (sDMARDs):
    • Methotrexate (MTX, Rheumatrex, Trexall)
    • MOA: Purine Antimetabolite, inhibits dihydrofolate reductase
    • Most predictable benefit and well tolerated in RA
    • Give with Folic Acid
    • May continue through surgery w/o stopping
    • SE: Hypersensitivity Pneumonitis, cytopenias even at low doses, abnormal LFTs, Infections, mucosal ulcers, GI, Abortifacient, alopecia, skin nodules, nephrotoxicity, macrocytic anemia, hepatotoxicity, stomatitis
      • May activate hepB or C, myelosuppression
    • CI: pregnancy, moderate to advanced renal disease, chronic liver disease, heavy alcohol use, parenchymal disease
    • Cycle off for ≥1 ovulatory cycle prior to pregnancy, 3 months for males
    • Methotrexate Pneumonitis
      • CXR w/interstitial infiltrates
      • Not dose related
      • Usually within 1st year
      • Subacute w/cough, dyspnea, fever
      • Bronchoscopy with BAL usually needed to R/O infection
      • TX: Stop MTX, taper with glucocorticoids
    • Get CXR, CBC and CMP, Viral HepB/HepC titers
      • CMP/CMP every 4 weeks for 3m, then every 3m
      • PFTs if COPD or dyspnea
    • PCN/sulfa decrease renal excretion
    • Folate supplementation
    • Azathioprine (AZA)
    • Thiopurine
    • First metabolized to 6-MP by the liver
    • Then metabolized by 3 pathways
      • 1) TPMT converts 6-MP to 6-MMP
      • Main pathway, inactive in 11% of population
      • 2) HPRT states conversion of 6-MP to 6-TG
      • Bone marrow suppression if high or on XO inhibitors, monitor CBC/LFTs
      • Hepatotoxic levels of 6-MMP if defective
      • 3) XO converts 6-MP to 6-TU
    • More commonly used for SLE and IBD
    • Test for TPMT (Thiopurine methyltransferase) prior to initiation of 6-mp or aza
    • Safe in Pregnancy
    • SE: Cytopenias, hepatotoxicity, GI
      • Increases risk of bone marrow toxicity
      • Dose-dependent diarrhea, leukopenia, hepatotoxicity
    • Cyclosporine A (CYA)
    • Calcineurin Inhibitor, inhibits T-cell production of IL-2
    • Synergistic with MTX
    • SE: Renal toxicity, hypertension
    • Cyclophosphamide (CYP)
    • Alkylating agent, disrupts DNA replication
    • SE: malignancy, infertility, infections, cytopenia, hemorrhagic cystitis
    • Hydroxychloroquine (HCQ, Plaquenil)
    • MOA: TNF & IL-1 suppressor
    • Antimalarial
    • Safe in pregnancy
    • May continue through surgery w/o stopping
    • SE: Retinal toxicity, neuromyopathy, hyperpigmentation
      • Annual eye exam after 5 years of continuous use
      • Increased retinal tox risk:
      • Retinopathy more likely with renal or liver disease
      • ≥60 y/o, ≥400mg/day, use ≥5 years, underlying retinal or macular disease
      • May exacerbate psoriasis
      • CBC/CMP every 3-6m
      • Initiation has an increased risk of MACE/CV mortality/MI vs. Methotrexate in HF patients
    • CI: G6PD deficiency
    • Leflunomide (LEF, Arava)
    • MOA: Antimetabolite, pyrimidine synthesis inhibitor
    • Initial DMARD in patients unable to take MTX
    • Same baseline studies as MTX
    • May continue through surgery w/o stopping if minor, stop 1-2 days before major surgeries, restart 1-2 weeks after
    • SE: Pneumonitis, cytopenias, hepatotoxicity, Infections, GI
    • CI: pregnancy, lactation, teratogenic
      • Give cholestyramine 8g PO TID for 11 days to eliminate drug (want leflunomide \<0.02mg/L for 2 tests 14 days apart)
      • Extremely teratogenic
    • Mycophenolate Mofetil (MMF)
    • Reversibly inhibits IMP Dehydrogenase, preventing purine synthesis of B and T cells
    • SE: GI upset, pancytopenia, hypertension, hyperglycemia, less nephrotoxic and neurotoxic
      • Teratogenic
      • Associated with invasive CMV infection
    • Sulfasalazine (SSZ, Azulfidine)
    • Antibiotic/Anti-inflammatory
    • RA and IBD
      • Sulfapyridine produces effects for RA
      • 5-ASA produces effects for IBD
    • SE: Cytopenias (check G6PD prior), Hepatotoxicity, oligospermia in 80% but reversible, rash, N/V/D/Ab pain, hemolytic anemia
    • Give folic acid supplements
    • May continue through surgery w/o stopping
    • Reyes syndrome in pts given varicella vaccine
    • Relatively safe during pregnancy
    • CI: G6PD deficiency
    • Tofacitinib (Xeljanz)
    • Small-molecule JAK-⅓ inhibitor
      • Inhibits intracellular signaling involved in T-cell activation, proinflammatory cytokine production, cytokine signaling
    • Refractory RA
    • SE: Infections (shingles particularly), Hyperlipidemia, cytopenias, TB reactivation, Abnormal LFTs if used with MTX
    • Biologic Agents (bDMARDs):
    • Screening: HepB, HepC, TB
    • Vaccinate with flu, pna, other vaccines
    • Avoid live attenuated vaccines (nasal flu, MMR, shingles)
    • Suspend biologic therapy during perioperative period

    • Anti-TNF Biologics:

      • Monoclonal antibodies that bind and inactivate TNF
      • Best used with MTX to halt and possibly reverse disease
      • Use: IBD, Rheumatoid Arthritis
      • Moderate to High risk patients: \<30, extensive involvement, perianal ± rectal disease, deep ulcer, prior surgery, structuring ± penetrating behavior
      • SE: drug induced lupus, CNS demyelination, worsening HF, malignancy, infection
      • CI: HF class III/IV, no live vaccines
      • TNFi + Thiopurine (azathioprine or 6-MCP) = increased risk for hepatosplenic T-cell lymphoma
        • Adalimumab (Humira)
      • Humanized Monoclonal Antibody
      • Soluble TNF-alpha inhibitor
      • Subcutaneous
        • Certolizumab (Cimzia)
      • Fab' segment of humanized monoclonal antibody attached to polyethylene glycol strands
      • Soluble TNF-alpha inhibitor
      • Subcutaneous
        • Etanercept (Enbrel)
      • Fusion protein made of two p75 TNF-alpha receptors linked to IgG Fc segment, Soluble TNF receptor linked to IgG1 (not a monoclonal antibody)
        • Golimumab (Simponi)
      • Humanized Monoclonal Antibody
      • Soluble TNF-alpha inhibitor
      • Subcutaneous
        • Infliximab (Remicade)
      • Chimeric (mouse-human) Monoclonal Antibody
      • Soluble TNF-alpha inhibitor
      • SE: Arthralgias (MC)
        • Non-TNF Biologics:
        • Abatacept (Orencia)
      • Soluble CTLA-4 receptor/IgG Fc segment chimera co-stimulation inhibitor (CD80 and CD86)
      • Blocks communication
      • Inhibits T-cells
      • Does not block TNF-alpha
      • SE: COPDE, infections, Nausea, Sinus infection, pneumonia, TB, Hyperglycemia
      • Associated with COPD exacerbations in vivo
      • Can't be used with biologics
        • Anakinra (Kineret)
      • Recombinant receptor antagonist
      • IL-1 antagonist
      • Less efficacious than other biologics
      • Requires daily injection
      • Continue for minor procedures, stop 1-2 days before major surgeries, restart 10 days later
      • SE: Neutropenia, infections, injections site reaction
        • Belimumab
      • Humanized Monoclonal Antibody
        • Canakinumab
      • Humanized Monoclonal Antibody
        • Rilonacept
      • Dual IL-1B receptors chimerically attached to IgG Fc segment
        • Rituximab (Rituxan)
      • MOA: Chimeric (mouse-human) Monoclonal Antibody to CD20 surface Ig of B cells
      • Stop 7 months before major surgery
      • Use: CD 20+ NHL, CLL, ITP, RA
      • Used with MTX, when refractory to TNFi
      • SE: Serious infections (increased risk of PML), SJS/TEN, HepB reactivation, serious infusion reactions, pulmonary toxicity
        • Secukinumab
      • Humanized Monoclonal Antibody
        • Tocilizumab (Actemra)
      • Humanized Monoclonal Antibody
      • IL-6 receptor antagonist
      • Refractory to DMARDs ± TNFi
      • SE: infections, hyperlipidemia, cytopenias, Diverticulitis/perforation, abnormal LFTs
      • Increases risk of bowel perforation in pts w/history of diverticulitis
      • Decreases efficiency of oral contraceptives
        • Tofacitinib
      • Oral targeted Synthetic Janus Kinase inhibitor
      • SE: Increased risk of thrombotic events
        • Ustekinumab (Stelera)
      • Humanized Monoclonal Antibody
      • Anti-IL-12/23 antibody
      • Used in high risk resistant crohns for induction and maintenance
      • Stop 1 week before procedure, restart ≥14 days later
      • Acetaminophen (Tylenol)
      • Metabolized within hepatic microsomes, predominantly by phase II reactions
        • 90% by Glucouronidation and Sulfination to nontoxic conjugates
        • 5% by P450 oxidation to NAPQI
        • Hepatotoxic metabolite, usually conjugates to glutathione
        • 5% by Direct urinary excretion
      • Toxicity
        • RF: Malnutrition (decreased GSH), fasting, P450 induction
      • Poisoning
        • Stage I (30 minutes to 4 hours)
        • Asymptomatic to GI upset
        • LFTs normal
        • Stage II (24 hours to 72 hours)
        • Initial symptoms resolve
        • RUQ pain, hepatomegaly
        • Increased LFTs, PT/INR, Total Bilirubin
        • Stage III (72 hours to 96 hours)
        • GII upset, jaundice
        • CNS dysfunction (hepatic encephalopathy)
        • Bleeding diathesis
        • ± Acute renal failure
        • LFTs ≥10k, PT/INR increase, Total Bilirubin ≥4.0, Hyperammonemia, Hypoglycemia
        • MC time of death (MSOF)
        • Stage IV (4 days to 2 weeks)
        • Recovery
        • Labs normalize
      • W/U: Measure Acetaminophen concentrations at 4 and 8 hours post ingestion
      • Treatment
        • Rumack-Matthew Nomogram
        • To predict toxicity and need for N-acetylcysteine for acute overdoses
        • Activated Charcoal if within 4 hours (1g/kg)
        • N-acetylcysteine if within 8 hours
        • Regenerates hepatic glutathione stores (IV ≥ oral in failure, prior to LFTs)
        • Death and hepatotoxicity uncommon if NAC given within 8hrs
      • Triptans
      • General
        • CI: Brainstem or hemiplegic Auras
      • Sumatriptan (Imitrex)
        • 3 methods of delivery (injection, intranasal, oral)
        • Combo: Sumatriptan + Naproxen
        • Works better than either alone
      • Zolmitriptan (Zomig)
      • Rizatriptan (Maxalt)
        • Works the fastest
        • Propranolol increases blood levels (downward titrate)
      • Almotriptan (Axert)
      • Eletriptan (Relpax)
      • Fovatriptan (Frova)
      • Naratriptan (Amerge)
      • CI: complicated or basilar migraines, CHD or Prinzmetal angina, Stroke history, uncontrolled BP, pregnancy, MAOIs within 24hrs