Non-Opioid Pain Relievers

Valerie Prince, Pharm.D., FAPhA, BCPS McWhorter School of PharmacySamford UniversitySt. Vincent’s East Family Practice Residency Program

Disclosures

I have no financial or other relationship to businesses or entities that are conflicts of interest and/or sources of bias regarding content of this presentation.

Learning ObjectivesPharmacists Design an appropriate therapeutic plan for pain management

which includes the safe and effective use of acetaminophen. Evaluate the risk: benefit ratio of potential NSAID use in a pain

management regimen. Choose appropriate antidepressant and/or anticonvulsant

medications for pain management based on patient specific factors.

Technicians Recognize appropriate minimum and maximum safe

acetaminophen doses. List 3 adverse effects of NSAID use. Name 3 antidepressant and 3 anticonvulsant medications used

for pain management.

Nociceptive Pain (Somatic & Visceral) Somatic pain comes from skin, bone, joint,

muscle, or connective tissue Visceral pain comes from internal organs

(intestine, pancreas) EX: Post-surgical, bone pain, pain due to

trauma Sharp, dull, aching, throbbing are common

descriptors

Neuropathic Pain

Results from damage to nerves or pathologic changes in the peripheral or central nervous system.

EX: Post-herpetic neuralgia, peripheral neuropathies, complex regional brain syndrome

Burning, tingling, shooting, electrical are common descriptors

Characteristics of Neuropathic Pain Hyperalgesia = Increased pain response to

normal stimuli Allodynia = Pain response to non-painful

stimulus Paresthesias = Tingling and/or “pins and

needles” feeling Dyesthesias (abnormal sensations such as

crawling skin or numbness) Spontaneous pain

Case: Effects of Pain A 58 yo is hospitalized for

pancreatitis. He assesses his pain as 7/10. His admitting physician writes an order for morphine 1mg IV q 6 hours prn. PMH: Migraines, Dyslipedemia, GERD. Home meds pantoprazole and atorvastatin. BP 160/98, P 98, SCr 1.3, BG 200, AST 35. Which of the labs/vital signs could be the result of unrelieved pain?

Physiological Effects of Unrelieved Pain

System Response Clinical Manifestation

Endocrine/Metabolic Altered hormone release (cortisol, insulin, etc)

Wt loss, Fever, RR, HR, Shock

CV BP, MO2 demand, hypercoagulation

Unstable angina, MI, DVT

Physiological Effects of Unrelieved Pain

Respiratory Air flow Atelectasis, Pneumonia

GI Rate gastric emptying, intestinal motility

Delayed gastric emptying, constipation, anorexia, ileus

Musculoskeletal Muscle spasm, impaired mobility and function

Immobility, weakness, fatigue

Physiological Effects of Unrelieved Pain

Immune Impaired immune function

Infection

Genitourinary Abnormal release of hormones that affect UOP, fluid volume, electrolyte balance

UOP, Hypertension, Electrolyte disturbances

World Health Organization Analgesic Ladder

Patient Scenario

AM is a 57 YOF who is admitted with fractured ribs secondary to a MVA. Her UDS is positive for alcohol and benzodiazepines and she admits to using both daily for the past several months. She describes her pain as severe. Pertinent abnormal labs include: AST 120, ALT 156. SCr 1.7. She has a standing order for Norco 7.5/325 1 – 2 q 4 – 6 hours prn pain. Are you comfortable with this order and do you have any recommendations?

Acetaminophen Can be monotherapy for mild to

moderate pain; Adjunctive with opioids in severe pain

+Analgesic, +antipyretic PO and IV >2gm/day X 7 days = ↑ INR (in the

presence of warfarin therapy) Hepatic toxicity

- DNE 4 gms/day or 2 gms/day with risk factors. Risk factors include liver disease, chronic alcohol use or binge drinking, and fasting.

OTC products 3gm/day dosing limit.

Patient Scenario: NSAID

37 yo female with a painful orthopedic injury reports that the ibuprofen 600 mg q 8 hrs that you gave her doesn’t adequately control her pain. She tells you she’s heard that “Naprosyn is better” and asks if she can try it. Would there be any benefit to changing to Naprosyn? What about increasing the dose of ibu to 800 q 8 hrs?

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Mild to moderate nociceptic pain +analgesic, +antipyretic, +anti-inflammatory Toxicities include GI, renal, platelet, sodium

and water retention. DI: ASA, HTN meds, Warfarin High doses extend duration of analgesia but

do not increase analgesic effect. MOA: Raises pain threshold by decreasing

sensitivity of nociceptors and by central mechanisms.

Patient Scenario

SP is an 86 YOF who is S/P THR. SCr 1.1 ABW 50 kg She reports her pain is severe. Her current standing orders for pain management include the following: Toradol 30 mg IV q 6 hours prn, Demerol 50 mg/Phenergan 25 mg IV q 4 hours. What concerns do you have and what changes (if any) would you make?

Ketoralac (Toradol) ***NSAID*** IV Toxicities same as PO NSAIDS 5 day limit on use (IV + PO) Reduce dose for wt < 50kg or age > 65 IV (q 6 hours) or IM (once)

administration Do not give to patients with ASA allergy PO not better than any other NSAID and

is more expensive than many other NSAIDs.

Neuropathic Pain TreatmentFirst Line Agents

Gabapentin (Neurontin®) Pregabalin (Lyrica®) Carbamazepine Valproic Acid TCA’s SNRI’s

Opioids are appropriate as second line agents

American Academy of Neurology (AAN) Guidelines: Diabetic Neuropathy Guidelines based on systematic review Bril V, England J, Franklin GM, et al.

Evidence-based guideline: Treatment of painful diabetic neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011.

Classified meds by efficacy grading.

AAN Guidelines

Effective Pregabalin 300 – 600 daily

AAN Guidelines: Probably Effective Agents Gabapentin Na Valproate Amitriptyline Duloxetine Venlafaxine Dextromethorphan Morphine Oxycodone

Tramadol Capsaicin Isosorbide dinitrate

spray

AAN Guidelines

Possibly Effective Agents :Lidocaine patch

Probably NOT effective: oxcarbazepine, lamotrigine, lacosamide, clonidine, pentoxifylline, mexilitine

Agent Selection in Diabetic Peripheral Neuropathic Pain

Factor AvoidGlaucoma, Orthostatic phenomena, Cardiac abnormality

TCA

Hepatic insufficiency

Duloxetine

Falls or balance issues

Pregabalin, TCA’s

Agent Selection in Diabetic Peripheral Neuropathic Pain

Depression Oxycodone CR, Pregabalin

Anxiety Oxycodone CR

Suicidal Ideation

TCA’s, Oxycodone CR

Agent Selection in Diabetic Peripheral Neuropathic PainCost Duloxetine, PregabalinDrug Interactions

Duloxetine, TCA’s

Weight Gain

TCA’s, Pregabalin

Edema Pregabalin

Argoff CE., Backonja MM, Belgrade MJ, et al. Diabetic peripheral neuropathic pain consensus guidelines: Treatment planning and options. Mayo clin proc.2006;81(4,suppl):s12-s25.

AED’s: Gabapentin, Pregabalin, Carbamazepine, Valproic acid

Start with low dose at bedtime, titrate over 4 – 8 weeks

Slow onset and full effect: 2 months adequate trial

Class effects include sedation, N, mental cloudiness, dizzyness

Carbamazepine/Oxcarbazepine – DOC trigeminal neuralgia, less effective otherwise

Pregabalin Adverse Effects Most common: Dizziness

somnolence, and peripheral edema. Others: Vertigo, incoordination,

ataxia, diplopia, blurred vision, sedation, and confusion.

May be habit forming (Schedule V)

Pregabalin

Initiate at 50 mg PO BID Titrate slowly (over a minimum of one

week) to150 mg PO BID Alternative dosing 100 mg TID Euphoric effect Expensive

Antidepressants in Neuropathic Pain TCA’s and SNRI’s Provide pain relief independent of

depression NNT in most AD trials is 2 – 3 Analgesic effects occur after about 1

week (SNRI) to 2 weeks (TCA); full effect usually seen in 6-8 weeks

Analgesic effects occur at lower doses for most agents (exception venlafaxine)

TCA’s in Neuropathic Pain Similar in efficacy to AEDs and duloxetine Best for burning pain or hypersensitivity May also be useful for lancinating pain 30% of patients will experience 50% pain

reduction 6-8 weeks for adequate trial Start low and titrate up

TCA’s: Nortriptyline, Desipramine, Amitriptyline

Sedation, orthostatic hypotension, cardiac conduction, anticholinergic adverse effects

Dry mouth, sedation, mental clouding and other AE may diminish in days to weeks

Dose 1 – 3 hours prior to bedtime unless paradoxical insomnia occurs

International Association for the Study of Pain (IASP) Guidelines: Use with caution with ischemic cardiac disease or ventricular conduction abnormalities limit doses to < 100mg/day when possible obtain a screening EKG if older than 40 years

Dworkin RH, O'Connor AB, Backonja M, Farrar JT, Finnerup NB, Jensen TS, Kalso EA, Loeser JD, Miaskowski C, Nurmikko TJ, Portenoy RK, Rice AS, Stacey BR, Treede RD, Turk DC, Wallace MS. Pharmacologic management of neuropathic pain: evidence-based recommendations.

Pain. 2007;132(3):237.

SNRI’s in Neuropathic Pain Duloxetine (Cymbalta® )- Best data in class Titrate dose over 2 weeks to minimize

nausea Anticholinergic effects CI in liver disease or EtOH drinkers

Venlafaxine (Effexor®) – Variable data Target pain dose 200 mg/day At doses >225 mg/day NE activity may

cause unacceptable increases in HR and BP. Taper both when d/c to prevent withdrawal

Neuropathic Pain Case

A 72 yo patient presents with bilateral foot pain (burning, pricking sensation). PMH DM, DL, Gastroparesis, Orthostatic Hypotension, BPH, Depression. Organ function WNL. Insurance BCBS. What do you recommend for pain management? Agents to particularly avoid in this patient? Initial starting dose?

Neuropathic Pain Case Cont’d Assume the patient starts venlafaxine

37.5 mg daily. His dose is titrated weekly up to 150 mg daily. He presents to clinic one month after starting venlafaxine therapy and reports his pain as 6/10 which is unacceptable to him. He has experienced no adverse effects. What is your recommendation at this point?

Topical Lidocaine

Usually adjunctive therapy Most appropriate for well localized

neuropathic pain 5% Lidocaine gel Less expensive than patch

5% Lidocaine patch (Lidoderm®)

Capsaicin

Depletes substance P from sensory C fibers, producing analgesia after repeated dosing

Adjunctive therapy for neuropathic pain Major AE: burning, stinging, and erythema at the

site of application the first few days to weeks; may lead to intolerance in up to one-third of patients. Exacerbated by warm water & hot weather

Instruct patients to wash hands after application

Capsaicin 8% Patch (Qutenza – RX product) Administered under close clinician supervision;

apply as a single 60-minute application no more frequently than q 3 months; pretreat with topical anesthetic. May cause 1st-3rd degree chemical burns; use with caution in patients with uncontrolled HTN, CV events, cerebrovascular disease due to transient pain related increases in BP

Cream/Gel/Liquid/Lotion Must be applied three to four times per day over

the entire painful area for up to six to eight weeks before optimal pain relief can be achieved

Assessment #1 (Pharmacist) A 34 YOM patient complains of persistent burning pain in

localized areas where “shingles” were present 6 months ago. He reports the pain is worse if the area is touched even lightly (allodynia). PMH non-significant. Organ function normal. No insurance and low income job. Which of the following would be preferred agent (s)?

A. Duloxetine B. Pregabalin C. Capsacin Patch D. Amitriptyline

Assessment #2 (Pharmacist) Assume he is started on amitriptyline 10 mg daily. This

dose is titrated up to the 50 mg daily he required to achieve adequate pain relief. After one month, he reports his pain level is acceptable to him. However, he is very unhappy about the constant dry mouth and constipation he experiences while on amitriptyline. Which of the following actions would be best?

A. Change to duloxetine. B. Change to nortriptyline. C. Reduce amitriptyline dose to 10 mg daily. D. Change to capsaicin topical.

Assessment #3 (Pharmacist) Which of the following is/are TRUE regarding

ketorolac (Toradol)? (Select all that apply)A. May cause anaphylactic reaction in

patients with ASA allergy.B. Maximum duration of therapy is 10

days.C. IV administration not associated with

GIBD. Can cause AKI

Assessment #1 (Technician) Which of the following exceeds the

maximum safe acetaminophen dose for a non-fasting, EtOH abstaining, well nourished patient with normal organ function? (Select all that apply)

A. 5 grams dailyB. 6 grams dailyC. 7 grams dailyD. 8 grams daily

Assessment #2 (Technician)

Which of the following is/are common adverse effects of NSAIDs? (Select all that apply)

A. Increased potential to bleed anywhere in body

B. Renal damageC. Gastrointestinal bleedingD. Liver failure

Assessment #3 (Technician)

Which of the following is/are an anticonvulsant(s) commonly used for management of neuropathic pain?

A. DuloxetineB. Valproic acidC. AmitriptylineD. Pregabalin