Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

Disclosures

Speakers Bureau: Allergan, Lilly, Salix Rational Polypharmacy for the Treatment of Pain

Any unlabeled/unapproved uses of drugs or products referenced will be disclosed. Theresa Mallick-Searle, MS, ANP-BC Stanford Health Care, Division Pain Medicine [email protected]

@tmallic https://www.linkedin.com/in/theresa-mallick-searle

Confidential – For Discussion Purposes Only

Objectives

clinical indications, contraindications & Explore dosing for common non- analgesics.

Describe where analgesics act in the pain pathway.

use of medication assisted therapy (MAT) Evaluate in pain management.

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What is Pain? Chronic Pain: Not Simply Acute Pain Lasting Longer

“An unpleasant sensory & emotional experience associated with, or resembling that associated with, actual or potential tissue damage.” International Association for Study of Pain (2020)

“Pain is a complicated process that involves an intricate interplay of chemicals and signaling on the central nervous system.” Sean Mackey, MD

“Whatever the experiencing person says it is, existing whenever he/she says it does.” McCaffery, RN

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1 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

Pain Types Categorized by Predominant Etiology The Neuromechanisms of Pain

•Fibromyalgia •Restless legs syndrome Peripheral Pain •Interstitial cystitis •Headaches Modulators: •Temporomandibular joint disorder • Histamines • Prostaglandins • Cytokines • Musculoskeletal pain • Sensory • ►Osteoarthritis and gout Hypersensitivity •Postherpetic neuralgia • Others ►Neck and back pain with / Nociplastic •Diabetic peripheral structural pathology neuropathy Descending ►Rheumatoid arthritis Mixed •Spinal stenosis Neurotransmitters: • Tumor-related • Serotonin •Spinal cord injury nociceptive pain Nociceptive Neuropathic • Norepinephrine •Chemo-induced neuropathy • Endogenous opiates • Others

•Back pain • Osteoarthritis • Fibromyalgia •Malignancy pain • Rheumatoid arthritis

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MEDICATIONS FOR PERIPHERALLY MEDIATED Non-opioid Analgesics VERSUS CENTRALLY MEDIATED PAIN • Anticonvulsants  • Antidepressants  Other: Peripherally Centrally Mediated Pain: Mediated Pain: • Muscle relaxants − Opioid /antagonists • Topical − • Acetaminophen • Alpha-2 analgesics/anesthetics • • Anticonvulsants − • Ca+ channel • NSAIDs • Acetaminophen/NSAIDs − low-dose naltrexone (LDN) • antagonists  mABs (calcitonin gene related • Topical • NMDA • Other adjuvants - sleep peptide – CGRP). anesthetics • Opioids aids, benzodiazepines • TCA/SNRI antidepressants  Other – supplements/nutraceuticals

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Polling Question Anticonvulsants

Rational Polypharmacy is?  First-line therapy in neuropathic/central pain syndromes.

a) The best way to justify your  The peripheral hyper-excitability is due to a series of use of opioids when the DEA molecular changes at the level of the peripheral nociceptor, agent comes knocking. in dorsal root ganglia, in the dorsal horn of the spinal cord, and in the brain. b) A way to safely and effectively use medications that make sense together in the  These changes include: treatment of pain. . Abnormal expression of sodium channels c) Part of a multimodal treatment . Increased activity at glutamate sites approach to pain management. . Changes in gamma-aminobutyric acid inhibition (GABA-ergic) d) A tag phrase unique to . Alteration of /sodium influx into cells PAINWeek. Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

2 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

GENERIC USES IN PAIN DOSING CONSIDERATIONS GENERIC (BRAND) USES IN PAIN DOSING CONSIDERATIONS (BRAND) NAMES NAMES

• Diabetic 600-3600 mg/d- - Sedating, weight gain, peripheral Neuropathies 600-2400 mg/d- - Serious dermatological reactions peripheral TID dosing edema, mood instability. (central/peripheral) BID dosing (Stevens-Johnson syndrome). (Neurontin) neuropathy - Growing recreational use. (Trileptal) Similar to - Mood changes, aplastic anemia, • Fibromyalgia - Renal excreted (100% thrombocytopenia, • Post-herpetic unchanged). hypernatremia, monitor -BUN/Cr, neuralgia - modulator CBC w/diff, LFTs. • Other - modulator neuropathies • Restless leg • Headache Migraine 50-200 mg/d- - Weight loss, cognitive BID dosing dysfunction, renal dosing. (Topamax) - Sodium channel modulator, GABA Same as gabapentin 150-600 mg/d- - Similar to gabapentin (schedule agonist, (less likely in TID dosing V controlled substance, renal antagonist (Lyrica) restless leg or excreted 90% unchanged). headache) - Calcium channel modulator

Trigeminal neuralgia 200-1200 mg/d- - Serious dermatological reactions Neuropathies 100-400 mg/d- - Serious dermatological reactions carbamazepine (central/peripheral) BID dosing (Stevens-Johnson syndrome), BID dosing (Stevens-Johnson syndrome). (Lamictal) (Tegretol) - Mood changes, aplastic anemia, - Caution in liver or renal thrombocytopenia, monitor - dysfunction. BUN/Cr, CBC w/diff, LFTs. - Sodium channel modulator, - Sodium channel modulator, decreases presynaptic glutamate GABA receptor agonist, serotonin & aspartate release releasing properties

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Anticonvulsants Anticonvulsants

 Studied double-blinded, placebo-controlled trials. Neurocognitive . All anticonvulsants appear to have some neurocognitive effects.  Pearls: Baseline CBC, CMP, EKG, drug specifics, start low- . Psychomotor reaction time, word finding, memory. go slow, wean off, patient education.  Bone disease Suicidality . Increased risk of bone fracture remains unclear, r/t ↑catabolism of Vit. D &  FDA analysis of data from 199 clinical trials of 11 ↑PTH, intestinal Ca absorption inhibition, osteoclastic bone resorption stimulation. anticonvulsants showed a risk of suicidal thoughts or behaviors. . General risk factors – Female, post-menopausal, Caucasian & Asian, old age, use, low BMI, low Ca and Vit. D intake. Dermatologic . AED related risk factors – High dose, multiple drug regimens, duration of therapy, chronic illnesses, metabolic acidosis.  Stevens-Johnson syndrome, toxic epidermal necrolysis, 90% of cases occur within first 60 days, dose dependent, HLA B*1502 testing recommended (Asian ancestry). Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

Antidepressants Antidepressants

 Co-analgesics in neuropathic/central pain syndromes.  Antidepressants may also exert adjunctive therapeutic influences through histamine  The explicit way in which antidepressants are effective in pain receptors as well as modulation of sodium management remains unknown, suspected to be channels. multifactorial.

 Modulate mood and pain perception.  Most popular theory is that antidepressants exert their effects on serotonin & norepinephrine, particularly along the descending spinal pain pathways.

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3 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

GENERIC (BRAND) CLASS DOSING CONSIDERATIONS GENERIC (BRAND) CLASS DOSING CONSIDERATIONS NAMES NAMES

Tricyclic 25-150 mg/d - Uses: DPN, PHN, FM, duloxetine (Cymbalta) Serotonin norepinephrine 60-120 mg/d - Uses: FM, chronic antidepressant (TCA) Once daily dosing migraine. inhibitors (SNRI) Once daily musculoskeletal (MSK) (tertiary amine) - symptoms, dosing pain. arrhythmias. - Renal dosing & hepatic - Inhibits serotonin & milnacipran (Savella) 25-200 mg/d- considerations. norepinephrine uptake BID dosing - Similar in terms of efficacy, equally. pharmacodynamics & side effects profile. TCA 25-150 mg/d - Similar to amitriptyline, - Inhibits norepinephrine and (secondary amine) Once daily dosing less sedating. serotonin reuptake in CNS. (Pamelor) - More potent inhibitor of noradrenaline than of serotonin uptake. - Predictable therapeutic window (60-200 ng/ml). venlafaxine SNRIs 75-300 mg/d- - Uses: generalized BID dosing neuropathic pain, Migraine. TCA 25-300 mg/d - Uses & SE profile similar to - Renal & hepatic dosing (secondary amine) Once daily dosing above, less sedating, more desvenlafaxine (Pristiq) venlafaxine is metabolized 50-100 mg/d adjustments. (Norpramin) activating. to desvenlafaxine Once daily - May effect bleeding time. - Less predictable dosing - Similar in terms of efficacy, therapeutic window (100- pharmacodynamics & side 300 ng/ml). effects profile. - Inhibits reuptake of - Inhibits norepinephrine, serotonin & serotonin & dopamine norepinephrine. reuptake in CNS. - Superior efficacy than amitriptyline. Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

Antidepressants Antidepressants

Studied double-blinded, placebo controlled trials Cardiovascular Risk: Greater with TCAs

duloxetine – FM/DPN/chronic MSK Tachycardia milnacipran – FM Orthostasis venlafaxine – Migraine QTc monitoring – EKG amitriptyline – Migraine/PHN/FM Elderly

Side Effects Behavioral Health Risks . Abrupt discontinuation: w/d symptoms = . serotonin reuptake inhibition include: malaise/chills/myalgia's/mood destabilization. nausea/insomnia/tremor/sexual dysfunction.

. norepinephrine reuptake inhibition include: . Increased suicidality: Black boxed warnings, monitoring. hypertension/sweating/dry mouth/constipation.

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Antidepressants Antidepressants Serotonin Syndrome: Risk generally is low Bleeding Risk/SNRIs: Controversial data suggests Know the signs/symptoms: - de-amplification of platelet aggregation Hunter Criteria ( agent PLUS one of the following) - minimal risk of upper GI bleed as monotherapy - spontaneous clonus - increased risk in combination with NSAIDs - acid suppression therapy decreases risk - inducible clonus & agitation or diaphoresis - ocular clonus & agitation or diaphoresis Pearls

- tremor & hyperreflexia . Baseline CBC, CMP, EKG, drug specifics, start low-go slow, - hypertonia wean off, patient education. - body temperature above 38°C (100.4°F) . Complaints of parasomnias (vivid dreams, racing thoughts, etc.): r/t anticholinergic effects of antidepressants, reduced by Education to patient is IMPORTANT low-dose .

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4 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

GENERIC (BRAND) CLASSIFICATION DOSING CONSIDERATIONS Muscle Relaxants NAMES

cyclobenzaprine 5-10 mg TID, prn - Structurally similar to a TCA. (Flexeril) - Functions primarily at Acts at the descending inhibitory pain pathways. supraspinal levels, not at cord.

carisoprodol (Soma) 250-350 mg TID, - Schedule IV Central prn - Active metabolite (meprobamate) – wean to  Antispasmodics: Used for muscular pain & spasm acting at Nervous discontinue. System the level of the spinal cord or supraspinal level. diazepam (Valium) Depressants 2-10 mg TID, prn - Schedule IV - Wean to discontinue - benzodiazepines (diazepam) 250-500 mg QID, - non-benzodiazepines (cyclobenzaprine) (Parafon Forte DSC) prn

metaxalone 800 mg QID, prn Less sedating  Antispasticity agents: Used to reduce hypertonicity (Skelaxin) associated with upper motor neuron disorders (multiple methocarbamol 1000-1500 mg QID, prn sclerosis). (Robaxin) 100 mg BID, prn - Sodium channel modulation (Norflex) - Higher anticholinergic side effects. Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

GENERIC (BRAND) CLASSIFICATION DOSING CONSIDERATIONS NAMES Polling Question Centrally 20-80 mg/d - Selective GABA-B Acting TID, prn receptor agonist. Possible side effects of the Antispacisity - DO NOT abruptly d/c antidepressants discussed intra-thecal use. today include all EXCEPT the tizanidine 2-4 mg tid, Hypotension following? (Zanaflex) prn, Maximum 36 mg/d a) Anticholinergic symptoms (dry mouth, urinary retention, dantrolene 25-100 mg Black Box warning: Rare constipation). (Dantrium) Peripherally TID-QID, but serious Acting Maximum 400 hepatotoxicity - Antispacisity mg/d especially in women and patients >35 years of b) Tachycardia age. c) Improved mood

d) Increased risk of suicidality

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Muscle Relaxants Acetaminophen

 All equally effective for short-term relief of low back pain.  First synthesized in 1878, and introduced for medical use in 1883. Comes in many preparations both OTC (oral, rectal, topical), as well as in prescription formulations generally combined with opioids and as a branded intravenous  Not more effective that NSAIDs for acute low back pain. preparation (Ofirmev®).

 All recommended for 2-3 weeks at a time, attempt to avoid  Elevation of the pain threshold through central activation of on-going chronic use. descending serotonergic pathways.

 All sedating, hepatic & renal considerations, some degree of  Recommended maximum daily dose is no more than 4,000 anticholinergic side effects. milligrams (mg) from all sources. Caution in liver disease.

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5 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

Non-steroidal Anti-inflammatories (NSAIDS) Non-salicylate NSAIDs

Inhibiting the COX , which convert to  Non-specific analgesics, but greater effectiveness likely in inflammatory prostaglandin H2 (PGH2). Inhibits both peripheral & central cyclo- pains. oxygenase > reducing prostaglandin formation.  Marked individual variation in response to different drugs.  3 isoforms: COX 1-3  Drug to drug variability in toxicities only partly determined by COX I/COX II . COX I – constitutive in many tissues, physiological function. selectivity. . COX II – constitutive in some tissues (kidney, brain).  Significant CV history, CHF, renal insufficiency are strong relative . COX III – inhibition mediates the effects of acetaminophen. contraindications.

 Can counter act the ASA protection in CV disease and stroke.  OTC & RX formulations  Use lowest effective dose, consider PPI for gastro-protective therapy. . Celecoxib – COX II (meloxicam oral – low doses)  Comes in OTC & RX strengths; oral, topical, rectal. . Meloxicam IV 30 mg (once daily dosing) . – 2,400-3,200mg/d.

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Topical analgesics/anesthetics Topical analgesics/anesthetics

Pharmacokinetics of Transdermal Drug Delivery  Advantages . Controlled absorption & more uniform plasma drug concentrations.  High concentration within the patch for transdermal delivery . Bioavailability is improved by avoiding first-pass hepatic metabolism & to occur. enzymatic or pH-associated deactivation.  The energy for drug release is derived from the concentration . Options with poor or no oral intake. gradient existing between a saturated solution of drug in the . Increased flexibility in terminating drug administration by patch system and the much lower concentration in the skin; drug removal. Patient compliance is improved as patches are simple, non- invasive, and convenient. movement occurs by diffusion.  Limitations  Since there is a high concentration within the patch and a low . Local irritation or sensitization of the skin at the site of patch concentration in the blood, the drug will continue to diffuse, application. maintaining a constant concentration of drug in the . Possibility of unreliable absorption (too much/too little subcutaneous circulation. fat, poor peripheral blood flow, body temperature). . Cost.  Only apply to intact skin. Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

Lidocaine Sodium Channel Blocking & Oral

 Class 1b anti-arrhythmic, topical & local anesthetic Antiarrhythmic Agents

 Sodium Channel Modulation (Mexitil) - oral (Tambocor) - oral antiarrhythmic antiarrhythmic  Available in OTC (0.5-4%) & RX (5%)  Dosing (neuropathic pain):  Dosing: 100-400 mg daily in  Minimal detectable serum levels with prescribed use 150 mg – 300 mg qd-BID divided dosing

5% & 1.8% patch (bioequivalent)  Considerations:  Considerations:

FDA approved PHN • Baseline labs (Cr, electrolytes, • Baseline labs (Cr, electrolytes, No more than 3 patches concurrently EKG) EKG) 12hrs on/12hrs off • drug:drug interactions • drug:drug interactions  IV Lidocaine 1mg/kg/hr. for acute neuropathic pain. • highly bioavailable = take with • black-box warning food +/- antacid

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6 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

Capsaicin Non-steroidal Anti-inflammatory Drugs

OTC preparations (0.025-0.075% cream) & RX 8%  Diclofenac

- Neuropathic pain, arthritis . 1.3% patch (Flector), 1 patch bid - Initially stimulates, then desensitizes & degenerates cutaneous nociceptors . 1.5-2% solution/spray (Pennsaid), 2 sprays BID - Down regulates substance P - Avoid touching eyes, mucous membranes . 1% gel (Voltaren Gel), 2-4 g QID/Max. 32 g/d

Capsaicin 8% patch (Qutenza) . FDA approved PHN & DPN (feet)  Black Box Warnings: Cardiovascular Risk & GI Risk. . 1-4 patches per application, no more frequently than q3mo.  Numerous studies shown lower GI side effects & superior . Pre-treat with topical anesthetic. analgesic benefit with dose equivalent topical to oral NSAIDs.

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Menthol/Salicylate Compounded Creams

 OTC (BenGay, Icy Hot, Salonpas, etc.)  Rarely covered by insurance

 Arthritis, low back pain, strains & sprains.  Compounding Pharmacy (+/- to quality)  – stimulates TRPM8 receptors, producing cold sensation/counter irritation.  Example RX:

 Salicylates – Inhibits COX-1/COX-2, blocks prostaglandin Lidocaine 1% + 5% production, inflammatory/pain pathway. compounded into a cream.

− According to the American Association of Poison Control Sig: apply dime size to area of Centers' National Poison Data System, over 24,700 hands BID PRN pain. and non-aspirin salicylate exposures were reported in 2014, including 7411 single exposures to . Disp: 30 grams w/6 refills

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Cannabinoids Cannabinoids/Forms & Preparations

There is conclusive or substantial evidence that or Herb 3-22% THC dronabinol : 2.5/5/10 mg cannabinoids are effective: CINV - 5 mg oral q2-4hr x4-6 Hashish/Hash Oil • Treatment for chronic pain in adults (cannabis) doses/day Anorexia, AIDS-associated - • Improving patient-reported multiple sclerosis spasticity symptoms (oral 40-90% THC cannabinoids) 2.5-10 mg oral BID CBD Oil (less than 0.3% THC) There is moderate evidence that cannabis or cannabinoids are nabilone: 1 mg effective: nabiximols (Sativex THC:CBD) CINV - 1-2 mg oral BID • Improving short-term sleep outcomes in individuals with sleep disturbance Synthetic: associated with obstructive sleep apnea syndrome, fibromyalgia, chronic pain, (Epidiolex): and multiple sclerosis (cannabinoids, primarily nabiximols) dronabinol (Marinol) CIII 5 mg/kg oral BID Canadian Pain Society: Neuropathic pain, chronic nabilone (Cesamet) CII Dravet syndrome/Lennon- • First-line treatments = TCA & SNRI. Second-line = Tramadol & Gastaut syndrome/seizures controlled-release opioid analgesics. Third-line = Cannabinoids. associated with tuberous sclerosis complex Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

7 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

Other Drugs Other Drugs

DRUGS/CLASSES USE IN PAIN DOSING CONSIDERATIONS/ DRUGS/CLASSES USE IN PAIN DOSING CONSIDERATIONS/ COMMENTS COMMENTS clonidine Sympathetically TD patch Alpha2agonist, Calcitonin-salmon Bone pain, 100-200U/d Inhibits osteoclasts, maintained pain 0.1- efficacy better with nasal spray phantom limb, helps regulate calcium 0.3mg/d. epidural/intrathecal/IV complex via bone, use with delivery. (Kumar, regional pain calcium/vit. D. (Lyritis, 2014) syndrome 2002) Neuropathic pain • NMDA plays a role (CRPS) NMDA antagonists: 1. 10–30 mg in pain Bisphosphonates: Bone pain, 1. 300 mg IV Efficacy better with Face qd amplification. phantom limb, qd for 10 intravenous (IV) 1. memantine pain/headache 2. 45– • CNS side effects CRPS days. delivery, esophageal 400mg qd including 1. clodronate (Namenda) 2. alendronate 2. 7.5 mg IV issues, osteonecrosis CRPS 3. 20- hallucinations, qd for 3 jaw. (Mackey, 2007) 2.dextromethorph 30mg/2hr. serotonin days. Alt. an 4. 100– syndrome. 3. ketamine 200mg/d. • Best efficacy for 40 mg po qd 4. amantadine ketamine infusion. for 8 weeks.

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Sleep aids (non-benzodiazepines) Tramadol

GENERIC USES IN PAIN DOSING CONSIDERATIONS (BRAND) NAMES Tramadol is a synthetic opioid pain medication used to treat moderate to moderately severe pain, in adults. zolpidem tartrate sleep aid 5-10 mg, Sleep walking, memory (Ambien) 6.25-12 mg loss, CR tolerance/dependence. Schedule IV  It is a controlled IV substance eszopiclone sleep aid 1-3 mg Dizziness and loss of (Lunesta) coordination, dependence. Schedule IV  Binds to the μ-opioid receptor ramelteon melatonin receptor 8 mg  Inhibits the reuptake of serotonin and norepinephrine (Rozerem) agonist with high affinity for MT-1 and MT-2 receptors, sleep aid Zaleplon (Sonata) sleep aid 5-20 mg Schedule IV

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Buprenorphine Buprenorphine for chronic pain

Buprenorphine Suggested conversion strategies  Non-selective, mixed agonist–antagonist opioid receptor (buprenex/butrans/belbuca) from a pure mu agonist opioid (Webster, 2020; package insert) modulator, acting as a weak of the mu opioid  Mod-severe pain receptor w/strong binding affinity. Weak kappa receptor ~< 90 MME antagonist. − 300 mcg IM/IV q6-8hr. • Discontinue after last evening dose. − 75-900 mcg buccal • Initiate buprenorphine the next  Schedule III controlled substance. − 5-20 mcg/hr. TD patch morning (TD 10 mcg/hr or 150 mcg buccal BID)  Behaves differently than other opioids in this respect, as it  Black Box Warnings: • Titrate to pain • Supportive management (α2 shows a ceiling effect for respiratory depression. − Addiction, abuse, misuse, agonist, antiemetic, SAO) respiratory depression, concomitant  Slow onset, mild-moderate analgesic effect, and is very long use with CNS depressants, ~> 90 MME acting with a half-life of 24-60 hours. pregnancy, QTc prolongation, Liver • Ditto metabolism. • Initiate buprenorphine the next morning (TD 20 mcg/hr or 300  Blocks voltage-gated sodium channels via the local − Similar to full mu agonists mcg buccal BID) anesthetic binding site. Confidential – For Discussion Purposes Only MMEConfidential = –morphine For Discussion Purposesmilligram Only equivalents

8 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

Buprenorphine/MAT Acute pain management w/MAT

Buprenorphine (many)  The higher the dose (e.g. mcg v/s mg, 2 v/s 32), the greater the occupation of the mu receptor.  Medication-assisted treatment (MAT) is the use of medications in combination with counseling and behavioral therapies, which is effective in − At 32 mg of buprenorphine ~16% of mu receptors are available. the treatment of opioid use disorders (OUD) and can help some people to  T1/2 20-44 hour sustain recovery.  In patients receiving mcg dosing; continue & supplement with full mu-  Training: opioid agonist. (Webster, 2020) − Apply for a practitioner waiver to prescribe or dispense buprenorphine under the Drug Addiction Treatment Act of 2000 (DATA 2000).  MAT active w/mg dosing: (Harrison, 2018; Lembke, 2019) − https://www.samhsa.gov/medication-assisted-treatment/training- − Reduce dosing as much as possible, maintaining effective management materials-resources/apply-for-practitioner-waiver (+/-12mg) − Divide total dose into BID or TID dosing.  Other considerations (requirement of X-license to prescribe for MAT, not − Consider increasing buprenorphine with PRN dosing to target the pain. for pain management). − Depending upon dose, use full mu-agonist with high binding affinity (fentanyl).  Dosing is individual, generally daily dosing, 2-32 mg/d SL

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GENERIC (BRAND) USES IN PAIN DOSING CONSIDERATIONS Low-dose naltrexone (LDN) NAMES

Opioid antagonist and has been shown effective for treating some tramadol (Ultram) Moderate to 100-400 mg IR, 100- Weak opioid, weak SSRI, ↑ severe pain 300 mg ER risk seizures at higher central pain states (multiple sclerosis, fibromyalgia, CRPS, migraine, doses. Same side effects etc.) as any other opioid, withdrawal syndromes.  The best evidence for pain treatment shows that at low doses (4.5mg) Schedule IV controlled substance. naltrexone effectively reduces pain. [LDN is used off-label in the treatment of pain, requires compounding.] buprenorphine Opioid dependence 2-16 mg/d SL Schedule III controlled (Subxone/Bunavail) IV/IM dosing substance. Ceiling effect at  Immune modulation at the microglia cells within the central nervous available 32mg.

system. Buprenorphine Mod-severe pain 300 mcg IM/IV q6-8hr. ditto (Buprenex/Butrans/ 75-900mcg buccal  Reduction of pro-inflammatory cytokines as well as neurotoxic super- Belbuca) 5-20mcg/hr. TD patch oxides. Low-dose naltrexone Central pain Ill-defined mechanism of  The brief blockade of opioid receptors between 02:00-04:00, that is caused syndromes action: Glial cell by taking LDN at bedtime each night is believed to produce a prolonged (fibromyalgia, modulation/anti- multiple sclerosis, inflammatory/anti- up-regulation of vital elements of the immune system by causing an CRPS, stroke pain, immunogenic? increase in endorphin and enkephalin production. etc) Low side effect profile. Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

Ketamine Polling Question

Ketamine is an N-methyl-D-aspartate that at Any prescriber with an active low-dose has effective analgesic properties. DEA license can prescribe buprenorphine?  Adjuvant to opioid therapy

 neuropathic pain symptoms dominate the clinical picture a) True

b) False Dosing Side Effects

IV infusion 10-30 mg/hr. • Psychometric (vivid dreams, Oral 30-60 mg every 2 hrs. PRN hallucinations, inability to control thoughts, anxiety) • Nausea & vomiting • Hypertension & tachycardia

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9 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

mABs – CGRP Antagonists Other mABs/CGRP Antagonists

Migraine Prophylaxis Migraine Acute  galcanezumab (Emgality) monthly subcutaneous injection binds to cgrp molecule.  ubrogepant (Ubrelvy) 50-100 mg oral − binds to cprp receptor  erenumab (Aimovig) monthly subq. injection binds to cgrp receptor. − contraindicated concomitantly with strong CYP3A4 inhibitors  rimegepant (Nurtec-ODT) 75 mg oral  fremanezumab (Ajovy) monthly or quarterly subq. injection binds to molecule. − ditto

 Eptinezumab (Vyepti) intravenous infusion, given over 30 minutes every 3 months.  lasmiditan (Reyvow) 50-100-200 mg oral → serotonin (5-  Atogepant - oral CGRP receptor antagonist in development HT)1F receptor agonists – differs from triptans. for the prevention of migraine. Completed phase III trials. Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

Other mAB – In Clinical Development Supplements/Nutraceuticals/Nutrition

zavegepant (BHV-3500) is a third generation, small molecule CGRP General Rules of Nutrition receptor antagonist. The chemical properties make it a candidate potentially suitable for multiple routes of delivery, including nasal, subcutaneous,  Nutrition underlies illness & underlie healing, supports wellness inhalation or oral administration. (microbiome) For Acute & Preventive Treatment of Migraine  Correction of deficiencies April → FDA approved a Phase 2 study of zavegepant for the treatment of COVID-19 infection associated pulmonary complications. To assess the  Supporting to skeleton & soft issues (skin, cartilage, bone) potential benefits of CGRP receptor-blockade in mitigating an excessive immune response which in some cases can be fatal in COVID-19.  Low-allergenic & Low-inflammatory

tanezumab – phase III for cancer pain & regulatory review for  Certification symbols, such as a United States Pharmacopeia osteoarthritis pain. (USP) symbol, verifies that the product contains the ingredients in stated amounts and strength, is pure, meets limits for mAB that works by inhibiting the binding of nerve growth factor contaminants, and disintegrates quickly.

(NGF)Confidential – Forto Discussion its receptors.Purposes Only Confidential – For Discussion Purposes Only http://www.consumerlab.com/

Supplements/Nutraceuticals/Nutrition /Curcuma

Inflammation & Pain Determine the efficacy & safety of curcuma domestica extracts in pain reduction and functional improvement.  Saturated fatty acids activate skeletal muscle cells to release inflammatory mediators that trigger macrophages. 367 primary knee osteoarthritis patients with a pain score of 5 or higher were randomized to receive:  Pro-inflammatory cytokines induce genes in dorsal root ganglion neurons and increase pain.  ibuprofen 1,200 mg/day  C. domestica extracts 1,500 mg/day for 4 weeks  Ingestion of dietary supplements of n-3 fatty acids has been consistently shown to reduce both the number of tender joints The main outcomes were: on physical examination and the amount of morning stiffness in patients with rheumatoid arthritis.  Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total: pain, stiffness & function scores.  Adverse events (AEs) were also recorded. Disclaimer: Suggestions from existing research, any prescribing should be done (Kuptniratsaikul, et al., 2014) understanding the unique patient medical history/intolerances/medications/allergies. Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

10 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

Turmeric/Curcuma SUPPLEMENTS: CONSIDERATIONS Musculoskeletal Pain Glucosamine is likely safe when  The mean of all WOMAC scores at weeks 0, 2, & 4 showed Knee osteoarthritis: taken by mouth in studied doses, for a short time by healthy adults. significant improvement when compared with the baseline . 300-500mg glucosamine in both groups. . 500 milligrams three times sulfate daily up to 90 days. . 480mg glucosamine . 1,500 milligrams once daily up hydrochloride three times to six month.  The number of patients who developed AEs was no daily +/- chondroitin 40 different between groups. mg TID Glucosamine may also cause insomnia, drowsiness, dry mouth, Low back pain: constipation,  liver and kidney However, the number of events of abdominal pain/discomfort . 1500mg/d. glucosamine studies. was significantly higher in the ibuprofen group. Glucosamine & Chondroitin may Osteoarthritis (general): increase the risk of bleeding. . 1000-2000mg/d. Glucosamine may ↑ blood pressure (Kuptniratsaikul, et al., 2014) & blood (affecting insulin

Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only resistance).

SUPPLEMENTS: CONSIDERATIONS SUPPLEMENTS: CONSIDERATIONS Migraine Neuropathic Pain

Benfotiamine (B1 derivative) taken at the DPN: Balakumar P, et al. Pharmacol Res. 2010 oral dose of 300-600mg over the course of Jun;61(6):482-8. Side Effects = mild GI Riboflavin: 400 mg qd-TID Riboflavin/CoQ10 = Regulate the day, usually in two divided doses with complaints, “skin allergic reactions” mitochondrial dysfunction. meals (150mg or 300mg twice daily). CoQ10: 100 mg TID Alpha Lipoic Acid 600mg/daily DPN: Mijnhout GS, et al. Neth J Med. 2010 Apr;68(4):158-62. Side Effects = headache, : 400-600 mg Mg = Normalize brain nausea, skin rash. daily neuronal hyperexcitability.

Gamma-Linolenic Acid 480mg/daily DPN: Keen H, et al. Diabetes Care. 1993 Jan;16(1):8-15. Feverfew (MIG-99): 100- Anti-inflammatory properties. SE = nausea. 300mg qd-QID [0.2%-0.4% parthenolide] Vitamin C 500mg TID PHN: Kapoor, S. Korean J Pain. 2012 Jul; 25(3): 200–201.

Vitamin E 400mg & Eve Primrose 500- DPN: Ogbera, AO, et al. Indian J Endocrinol 1000 mg/day. Metab. 2014 Nov-Dec; 18(6): 846–849. Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

SUPPLEMENTS: Central Pain CONSIDERATIONS (FM, stroke, CRPS) Final Thoughts

Coenzyme Q10 100mg TID (see supplements for migraine)  Chronic pain management requires a multimodal approach, Acetyl L-carnitine 500mg/qd-BID Impacts mitochondrial function, thought to play a includes rational polypharmacy. significant role in peripheral nerve injury. Free radical scavenger & T-type calcium .  Opioids are still appropriate in 5-HTP 100mg TID Works in the brain & central nervous system by increasing the production of the chemical many situations, mindful approach. serotonin.  Knowledge of the pain pathways & Serotonin can affect sleep, appetite, temperature, sexual behavior, and pain various receptors → better sensation. understanding/appreciation/ Omega 3 fatty acids Antioxidant, anti-inflammatory properties. research/utilization of non-opioid for pain Vitamin C 500mg TID Antioxidant, anti-inflammatory properties. Creatine Reduces muscle damage by decreasing the management. http://www.mayoclinic.org/drugs- inflammatory response and oxidative stress, supplements/creatine/dosing/hrb-20059125 regulating calcium homeostasis, and activating satellite cells.  Patient/Clinician/Pharmacist Melatonin 3-6 mg Regulates the body’s sleep-wake cycle. education is needed.

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11 Rational Polypharmacy for the Treatment of Pain Theresa Mallick-Searle, MS, ANP-BC O5

Resources Selected References

 http://www.rxlist.com/script/main/hp.asp 1. ACPA – Stanford Resource Guide To Chronic Pain Management An Integrated Guide to Medical, Interventional, Behavioral, Pharmacologic and Rehabilitation Therapies 2020 Edition.  http://www.theacpa.org/Consumer-Guide file:///C:/Users/s0040168/AppData/Local/Microsoft/Windows/INetCache/IE/ROXKF XQ6/ACPA-Resource-Guide-2020-2-26-2020.pdf  WebMD has a Vitamins and Supplements Lifestyle Guide 2. Bajaj, S., Whiteman, A., Brandner, B. Transdermal Drug Delivery in Pain http://www.webmd.com/vitamins-and-supplements/lifestyle-guide-11/chronic- Management. BJA Education. 2011;11(2):39-43. pain-relief?page=1 3. Bell RF, Eccleston C, Kalso EA. Ketamine as an adjuvant to opioids for cancer pain (review). Cochrane Database Syst Rev 2012; 11:CD003351Blake A, Wan BA,  Vitamins & Supplements Malek L. A selective review of medical cannabis in cancer pain management. Ann Palliat Med. 2017;6(Suppl 2):S215-S222. http://www.webmd.com/vitamins-supplements/condition-1452-Pain.aspx?query 4. Bourdette, D. "Spotlight on low dose naltrexone (LDN)". US Department of Veteran  An article entitled Herbal Remedies: Adverse Effects and Drug Interactions Affairs. at http://www.aafp.org/afp/990301ap/1239.html and a patient handout https://web.archive.org/web/20120225220715/http://www.va.gov/MS/articles/Spotli ght_on_Low_Dose_Naltrexone_LDN.asp Accessed February 2, 2016. (Herbal Health Products--What You Should Know) 5. “Buprenorphine". Martindale: The Complete Drug Reference. London, UK: http://www.aafp.org/afp/990301ap/990301e.html) on the American Academy of Pharmaceutical Press. 14 January 2014. Family Physicians web site. https://www.medicinescomplete.com/mc/bnf/current/PHP2680-buprenorphine.htm

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Selected References Selected References

6. Cohen SP. Neuropathic pain: mechanisms and their clinical implications. BMJ. 12. Jonkman K, van de Donk T, Dahan A. Ketamine for cancer pain: what is the evidence? 2014;348:f7656. Curr Opin Support Palliat Care. 2017 Jun;11(2):88-92.

7. Finnerup, N., Sindrup, S., Jensen, T. The evidence for pharmacological 13. Kuptniratsaikul, V., Dajpratham, P., Taechaarpornkul, W., Buntragulpoontawee, M., Lukkanapichonchut, P. et al. Efficacy and safety of Curcuma domestica extracts compared treatment of neuropathic pain. Pain. 2010;150:573-581. with ibuprofen in patients with knee osteoarthritis: a multicenter study. Clin Interv Aging, 2014;9:451-8. 8. Furulie, C. Nutraceuticals for Diabetic Neuropathy. Advance for NPs & PAs http://nurse-practitioners-and-physician- 14. Lembke A, Ottestad E, Schmiesing C. Patients maintained on buprenorphine for opioid assistants.advanceweb.com/Features/Articles/Nutraceuticals-for-Diabetic- use disorder could continue buprenorphine through the perioperative period. Pain Neuropathy.aspx. Accessed February 5, 2016. Medicine, 2019;20:425-428.

9. Garland EL. Pain processing in the human nervous system: a selective review of 15. Mallick-Searle T. Commonly used nonopioid analgesics in adults. Nursing. 2018 May;48(5):61-63. nociceptive and biobehavioral pathways. Prim Care. 2012;39(3):561-571 16. MacCallum CA & Russo EB. Practical considerations in medical cannabis administration 10. Harrison TK, Kornfeld H, Aggarwal AK, Lembke A. Perioperative considerations and dosing. European Journal of Internal Medicine 2018;49:12–19. for the patient with opioid use disorder on buprenorphine, methadone or naltrexone maintenance therapy. Anesthesiology Clinics, 2018(36)3:345-359. 17. National Academies of Sciences, Engineering, and Medicine. 2017. The health effects of cannabis and cannabinoids: Current state of evidence and recommendations for research. 11. IOM. Relieving Pain in America: A Blueprint for Transforming Prevention, Care, Washington, DC: The National Academies Press. Education, and Research. Washington, DC: The National Academies Press; 18. Stanos S, Brodsky M, Argoff C, et al. Rethinking chronic pain in a primary care setting. 2011. Postgrad Med. 2016;128(5):502-515. Confidential – For Discussion Purposes Only Confidential – For Discussion Purposes Only

Selected References

19.Swarm RA, Paice JA, Anghelescu DL, et al. Adult Cancer Pain, Version 3.2019. J Natl Compr Canc Netw 2019;17(8):977–1007.

20.Turgeman I & Bar-Sela G. Cannabis Use in Palliative Oncology: A Review of the Evidence for Popular Indications. IMAJ 2017 Feb;19(2):85-88.

21.Webster L, Gudin J, Raffa RB, et al. Understanding Buprenorphine for Use in Chronic Pain: Expert Opinion. Pain Medicine, 0(0), 2020, 1-10.

22.Younger J., Parkitny L., McLain D. The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain. Clin Rheumatol. 2014; 33(4): 451–459.

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