NON-OPIOID PHARMACOLOGIC THERAPY FOR CHRONIC PAIN IN THE PRE-ANESTHETIC PATIENT

Amber Dewey, NP-C, MSN

April 10, 2015

amberld@earthlink.net

Objectives• Briefly discuss the current understanding of chronic pain,

as distinct from acute pain.• Discuss the various classes of non-opioid medications

used in the treatment of chronic pain, including mechanism of action, potential interactions with anesthetic agents, and potential concerns in the peri-operative patient.

Plan• Chronic Pain: What is it?• NSAIDs and Acetaminophen• Muscle Relaxers• Calcium Channel Blockers and other anticonvulsants• Anti-depressant type medications• Topicals

Pain• The 5th Vital Sign• … an unpleasant sensory and

emotional experience associated with actual or potential tissue damage, or described in terms of such damage.• International Association for the Study of

Pain, 1994

• The single most reliable indicator of the existence and intensity of pain and any resulting affective discomfort or distress is the patient’s self-report

Chronic Pain• 100 million people in the U.S. have chronic pain

• More than diabetes, CHD and cancer combined

• Chronic pain does not “look” like acute pain• Cannot maintain the sympathetic outflow seen in acute pain

• Results in neural rewiring and upregulation of pain receptors (“wind-up”) – increased neuronal activity

• Hyper-reactivity of nervous and immune systems• Chronic pain can be a disease in itself

• IOM Document: Relieving Pain in America 2011

Mechanisms of Drug Interactions• Pharmacodynamic

• Overlapping or synergistic mechanisms of action or adverse effects

• Pharmacokinetic• Alterations in or competition for metabolic processes or excretion

NSAIDs and Acetaminophen• Acetaminophen• Non-selective COX inhibitors

• Ibuprofen• Naproxen• indomethacin• nabumetone• Diclofenac• etodolac • Piroxicam

• Selective COX-2 inhibitors• Celecoxib• (Meloxicam)

NSAIDs and Acetaminophen• Pharmacodynamics – inhibition of cyclooxygenase (COX),

rate-limiting step in the formation of prostaglandins.• Arachidonic acid is converted by COX to prostaglandins,

with multiple effects throughout the body• Prostaglandin H2 is converted to pro-inflammatory compounds• Prostaglandin E2 in the CNS is involved in hypothalamic set point

for thermoregulation (fever), and in reducing activation of the descending inhibitory serotonin pathways (pain)

• COX-1 is present in all tissues; COX-2 is preferentially expressed at sites of inflammation

Acetaminophen• Not effective as an anti-inflammatory because is quickly destroyed

by high levels of peroxidase in inflamed tissues.• Thought to work primarily by inhibiting COX in the CNS – excellent

for pain and fevers. May also have an effect through endocannabinoid system and as NMDA receptor antagonist

• Pharmacokinetics: Hepatic metabolism – 3 routes• Glucuronide conjugation – 40-60%• Sulfate conjugation – 20-40%• Cytochrome P450 2E1 hydroxylation, then glutathione conjugation

• Propofol is eliminated primarily by glucuronidation and sulfation• Possibility for increased APAP toxicity, especially in patients with hepatic

impairment or cachexia

NSAIDs• Aspirin – irreversible inhibition of COX• Other NSAIDs – reversible, although some have very long

half-lives (piroxicam – 50 hours)• Prostaglandin functions

• Renal – decrease tubular reabsorption• Platelets – increase clotting• Stomach – gastroprotective• Uterus – contraction/relaxation• CNS – hypothalamic thermostat• Inflammatory mediators

NSAIDs• Most are highly protein bound, up to 99%• Metabolism is through various CYP 450 pathways and

glucuronidation• Toxicity in overuse

• Anion gap metabolic acidosis• Renal toxicity – acute renal failure, acute renal papillary necrosis

• Likely due to renal vasoconstriction

• Possible interactions• Other highly protein bound drugs – etomidate• Acidosis – increased potency of monoquaternary neuromuscular

blockers (rocuronium, vercuronium, tubocurarine)• Renal toxicity – drugs predominantly eliminated through renal

excretion (pancuronium)

Muscle Relaxers• Cyclobenzaprine (Flexeril)• Tizanidine (Zanaflex)• Methocarbamol (Robaxin)• Baclofen• Carisoprodol (Soma)• Chlorzoxazone (Parafon Forte)• Metaxalone (Skelaxin)• Orphenadrine (Norflex)• Magnesium

Muscle Relaxers• Act centrally and peripherally to reduce skeletal muscle

tone, depress spinal and supraspinal reflexes and inhibit ascending reticular formation

• Various mechanisms, mostly unknown exactly how they work

• Also provide an analgesic effect and usually some degree of sedation

Muscle Relaxers – Mechanism of Action

• Baclofen – GABA-B agonist, causes hyperpolarization by increasing K+ conductance, reducing Ca2+ influx

• Tizanidine – central and peripheral alpha-2 agonist, inhibits release of excitatory amino acid neurotransmitters

• Magnesium – inhibits ACh release peripherally• Orphenadrine – NMDA and histamine receptor antagonist,

centrally acting• Cyclobenzaprine – has tricyclic antidepressant activity as

well as muscle relaxer• Carisoprodol – some action may be due to anxiolysis

(meprobamate is 1st metabolite)• Others – pretty much completely unknown

Muscle Relaxers – Potential Interactions

• SEDATION – is a risk with all muscle relaxers. They are all sedating to some degree. There may be associated ataxia and confusion.• Abrupt discontinuation of centrally acting muscle relaxers is

generally contraindicated, due to potentially severe withdrawal effects

• Magnesium – may potentiate NMBDs, has been seen with vecuronium

• Tizanidine and etomidate – may be potentiation; both have alpha-2 agonist activity

• Intrathecal baclofen and etomidate – increased risk of seizure

• Dry mouth is often a problem with muscle relaxers, along with other anticholinergic effects.

Anti-convulsants• Gabapentin (Neurontin)• Pregabalin (Lyrica)• Carbamazepine (Tegretol)• Oxcarbazepine (Trileptal)• Divalproex (Depakote)• Others

Gabapentin and Pregabalin• Structurally related to GABA, but do not bind at GABA

receptor or work through the GABA-ergic system• Interact with alpha-2-delta-1 subunit of the voltage

dependent calcium channel on pre-synaptic neuron in the DRG

• Reduce calcium channel function => reduced release of neurotransmitters => reduced neuronal hyperexcitability

• Minimal effect on normal neuronal activity (pregabalin)• May also reduce glutamate synthesis (pregabalin)• Possible modulation of TRP channels, NMDA receptors,

protein kinase C, and inflammatory cytokines; stimulation of NE-mediated descending inhibition (gabapentin)

Gabapentin and Pregabalin• Almost no protein binding• Almost no hepatic metabolism• Excretion is almost completely renal

• Half-life is prolonged in people with reduced kidney function• Can be given in dialysis patients, but reduce dose and give after

dialysis

Gabapentin and Pregabalin• Most common adverse effects include sedation, dizziness,

ataxia, blurred vision, weight gain• May be associated post-operatively with respiratory

depression, headache• Abrupt discontinuation – may be increased risk of seizure

Oxcarbazepine and Carbamazepine• Mostly used for trigeminal neuralgia• Mechanism of action likely due to blockade of Na

channels, reduction in repetitive firing of Na-dependent APs

• Possible involvement of Ca, K channels, possible decrease in DA and NE reuptake

• Stabilization of neuronal membranes

Oxcarbazepine and Carbamazepine• Carbamazepine is a powerful inducer of CYP450 3A4• Oxcarbazepine also induces 3A4 and 3A5, inhibits 2C19,

but less than carbamazepine• Both undergo significant hepatic metabolism, both through

CYP450 system, then conjugation

Oxcarbazepine and Carbamazepine• Sedation, ataxia, blurred vision, etc• Aplastic anemia, agranulocytosis – mostly carbamazepine,

but has been reported with oxcarbazepine• Hyponatremia• Abrupt withdrawal – increased risk of seizures

Carbamazepine• Non-depolarizing NMBDs – reduced response, rapid

recovery – likely need higher dose, repeat dosing• Monitor closely!! • ? Increased clearance?• ? Decrease in affinity of nicotinic receptor for NMBD?• ? Increase number of nicotinic receptors?• ? Combination of above?• Literature suggests seen with vercuronium, pancuronium,

doxacurium, pipecuronium, rocuronium, cisatracurium• Not seen with atracurium, mivacurium

Valproic Acid• Divalproex sodium – Depakote• There are other formulations• Mostly used with migraine• Mechanism of action is probably related to GABA-ergic

effects, possibly by inhibiting GABA degradation or reuptake; may also block Na channels

• Highly protein bound

Valproic acid• Adverse effects

• Liver failure – highest risk in kids, has Boxed Warning• Thrombocytopenia, reduced platelet function, agranulocytosis• SIADH• CNS changes

• Increased risk of seizure with abrupt withdrawal

Anti-depressants• Tricyclics

• Nortriptyline, amitryptyline, desipramine, imipramine

• Venlafaxine (Effexor)• Milnacipran (Savella)• Duloxetine (Cymbalta)

Tricyclics• Serotonin and norepinephrine reuptake inhibition• Blockade of ion channels, reducing influx of Ca and Na• Interaction with adenosine and NMDA receptors• Blockade of alpha-1 and alpha-2 receptors - hypotension• Anti-histamine activity – sedation, weight gain• Muscarinic receptors – anticholinergic effects

• All have some activity at each site, but degree varies

Tricyclics• 90-95% protein bound• Extensive CYP 450 metabolism, then glucuronidation

• Sedation, weight gain, dry mouth, blurred vision, delirium (especially in elderly), constipation, urinary retention

• Abrupt withdrawal – “discontinuation syndrome”

Tricyclics• Potentially significantly increased sensitivity to

catecholamines• Sympathetic stimulation peri-operatively can lead to

hypertension and cardiac arrhythmias, post-operative confusion/delirium, ileus, urinary retention

• Avoid or use with caution: Epi, Norepi, atropine, pancuronium, ketamine, ephedrine, ketamine, meperidine

• Possibly increased seizure risk• Increased risk orthostatic hypotension, especially in

elderly

Serotonin syndrome• Usually seen with multiple medications that increase

serotonin activity• Tramadol!• Agitation, confusion, increased motor activity,

hyperthermia, tachycardia, labile blood pressure, diarrhea. Seizures, rhabdomyolysis, renal failure, arrhythmias, coma and death may occur.

• Catch it early, or avoid altogether

SNRIs• Venlafaxine, milnacipran, duloxetine• Serotonin and nortriptyline reuptake inhibitor

• Little to no anticholinergic, antihistamine or alpha receptor blockade

• Probably low risk in anesthesia

Topical pain medications• Lidocaine ointment, cream, gel, patches• Diclofenac cream, gel, patches (NSAID)• Compounded topical preparations (multiple medications)• Capsaicin creams, patches

Topical Pain Medications• Typically do not have much, if any, systemic absorption.

There may be very high tissue concentrations in the immediate area.

• If there is systemic absorption, pharmacodynamics, metabolism and excretion will be similar to oral forms of the medication.