Ch. 17 - Pharmacology of Pain

Jenny Koehl, PharmD, BCPS | Massachusetts General Hospital

Herein we discuss the pharmacology of commonly employed analgesic agents in the emergency department. This information will assist providers in selecting therapies with different pharmacologic mechanisms to target multiple pain pathways, reduce opioid usage, and avoid periods of inadequate pain relief. Within this strategy, around the clock dosing of medications is important to prevent the undertreatment of pain as well as lower the dose of medications overall.

ALTERNATIVES TO OPIOIDS (ALTO)

Acetaminophen
Acetaminophen (APAP) has antipyretic and analgesic effects but lacks peripheral anti-inflammatory properties. The antipyretic and a portion of the analgesic effects result from selective inhibition of a recently discovered COX-1 splice variant enzyme, COX-3, present in the brain and spinal cord.¹ COX-1 is constitutively expressed and is responsible for maintaining gastrointestinal (GI) mucosa, regulating renal blood flow, and platelet aggregation.² APAP easily crosses the blood brain barrier and is distributed throughout the central nervous system (CNS) allowing it to reach concentrations in the brain able to inhibit COX-3 enzymatic activity. APAP does not bind directly to the active site on the enzyme but reduces the active form and inhibits its catalytic activity.³

In addition to centrally-mediated COX inhibition, analgesic and antipyretic properties of APAP also stem from modulation of the endogenous cannabinoid system via the vanilloid and cannabinoid signaling.⁴ After de-acetylation to p-aminophenol, APAP undergoes conjugation with arachidonic acid to form N-arachidinoyl-phenolamine (AM404) in the CNS.⁵ The structures of AM404 and endogenous cannabinoid neurotransmitters are similar which allows the APAP metabolite to act as a weak agonist of cannabinoid receptors leading to increased levels of endogenous cannabinoids.^6-8 AM404 is also a potent activator of the vanilloid subtype 1 receptors whereby causing vasodilation.⁹

Acetaminophen is often administered with ibuprofen for acute pain presentations in the emergency setting where the combination of acetaminophen (1,000 mg) plus ibuprofen (400 mg) simultaneously was found to be superior to using either agent alone.⁴⁷ A 2017 study found the combination of acetaminophen/ibuprofen was as efficacious as the opioid-containing combinations oxycodone, hydrocodone, codeine plus acetaminophen when used for musculoskeletal pain in an emergency setting reinforcing its use over opioids in mild and moderate pain settings.⁹¹

Acetaminophen is listed as a Category B FDA rating for the first through third trimester of pregnancy secondary to a favorable safety profile (Black and Hill 2003; de Fays et al. 2015). In mild to moderate pain, acetaminophen is considered the safest first line analgesic for pregnancy and lactation.⁹⁴

Dosing: Daily doses of APAP should not exceed 4,000 mg or 3,000 mg in patients with a history of liver disease or the elderly. APAP can be given orally (PO), per rectum (PR), or intravenously (IV), although the IV preparation is expensive and lacks data to suggest superior clinical efficacy.¹⁰

Non-steroidal anti-inflammatory drugs
Non-steroidal anti-inflammatory drugs (NSAIDs), unlike APAP, are competitive inhibitors of COX-1 and COX-2 which mediate the conversion of arachidonic acid to inflammatory prostaglandins. NSAIDs reduce the levels of prostaglandins in the central and peripheral nervous system, relieving pain, swelling and redness. NSAIDs also inhibit prostaglandin-mediated stimulation of the hypothalamus which results in a lowering of body temperature.²

Traditional NSAIDs block prostaglandin synthesis via non-selective inhibition of COX-1 and COX-2 isozymes. These agents include aspirin, ibuprofen, naproxen, and ketorolac. Within this non-selective class, aspirin is unique in that it irreversibly inhibits the COX enzymes, whereas the rest of the class competitively inhibits the active site. This results in aspirin's platelet aggregation inhibition lasting the lifespan of the cell. As COX-1 is responsible for maintaining gastrointestinal (GI) mucosa, regulating renal blood flow, and platelet aggregation, side effects of the non-selective NSAIDs include nausea and vomiting, gastric ulceration, bleeding, and kidney injury.¹¹ There are a few agents that are non-selective but have a higher affinity for the COX-2 enzyme and these include indomethacin, meloxicam, and diclofenac. Second generation NSAIDs are selective COX-2 inhibitors, with the COX-2 isoenzyme only expressed during times of inflammation. This selectivity results in an improved gastric safety profile; however, COX-2 selectivity has shown to increase risk of myocardial infarction, stroke, and heart failure resulting from induction of a pro-thrombotic state.¹² Celecoxib is the only COX-2 selective NSAID currently available on the market as other agents have been removed due to their increased cardiovascular (CV) risks.

Summary: COX-3 is associated with centrally mediated analgesic and antipyretic properties, but low anti-inflammatory activity. COX-1, the precursor to COX-3 has similar properties but may be targeted centrally and peripherally. COX-2 is involved with the inflammatory process and NSAIDs that inhibit COX-2 are best for pain resulting from inflammatory states.

When selecting an NSAID one must weigh the GI, renal, and CV risks. If the patient is at higher risk of a GI bleed consider adding a proton pump inhibitor to reduce risk of GI bleed.

All NSAIDs have an analgesic ceiling dose, which is lower than the anti-inflammatory maximal dose. When the ceiling dose is met, additional increases in dose provide no further analgesic benefit. This ceiling dose has been reported as 1,0000 mg for aspirin and acetaminophen, 400 mg for ibuprofen, and 10 mg for IV ketorolac.^13-15 Yet higher doses may be needed to achieve additional anti-inflammatory benefits. With this in mind, lower dosages should be selected for noninflammatory pain, and higher ranges are reserved for those situations in which inflammation and swelling are significant contributors to pain. 

Topical NSAIDs may also be considered. As opposed to PO and IV analgesics which require systemic distribution, topical/transdermal analgesics use localized analgesic distribution to limit total-body quantities delivered.^76,109,113 Topical NSAIDs can preferably accumulate in targeted areas such as cartilage and meniscus with concentrations 4-7 times greater than plasma concentrations, and in tendons with concentrations one hundred times greater than plasma concentrations.⁷⁶ Topical analgesics are optimal in patients with renal disease or elderly patients susceptible to elevated analgesic plasma concentrations and in patients with multiple comorbidities such as peptic ulcer disease and cardiovascular disease in which PO NSAIDs are relatively contraindicated.⁸⁵

Examples of topical analgesics include diclofenac, ketoprofen, and ibuprofen. Pain pathologies that benefit from topical analgesics include acute sprain, strain, overuse injuries, contusions, tendinopathies, bursitis, exacerbations of osteoarthritis.¹⁰⁷ Adverse effects include milder GI disturbance, hemorrhage risk, renal dysfunction, bronchospasm, delayed wound healing headache.¹¹⁰

Sub-dissociative Ketamine
Ketamine is an analgesic adjunct often used for pain management in the setting of intractable pain, neuropathic pain, or opioid-tolerant and opioid-induced hyperalgesic states. Once in the blood stream ketamine redistributes to the CNS in about 30-45 seconds resulting in a very rapid onset of action. When using ketamine for pain a sub-dissociative dose of 0.1–0.3 mg/kg IV as a single dose given over 10-15 minutes, 0.15 mg/kg/hr as a continuous infusion, or 0.7–1 mg/kg intranasal should be employed.¹⁶ Ketamine is highly water soluble with high lipophilicity and should be dosed based on ideal body weight.

At these lower doses, ketamine acts as a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist in the brain and spinal cord²⁴ as well as a partial mu receptor agonist. This results in pain relief as the NMDA receptor is involved in the amplification of pain signals, the development of central sensitization, and opioid tolerance.²³ Additionally, ketamine has been shown to have anti-hyperalgesic effects that may reduce or reverse opioid tolerance.^25,26

Ketamine's adverse effects are dose-dependent. At sub-dissociative doses ketamine may result in psychoperceptual side effects, a feeling of unreality, sedation, nausea, vomiting, dizziness, and nystagmus (seen shortly after onset). These adverse effects have been shown to be decreased when administered as an infusion over 10-15 minutes rather than a bolus dose.¹⁷ Selecting doses at the lower end of the dosing range will minimize adverse effects particularly in the geriatric population (Motov, 2018). At higher doses ketamine also acts on dopamine₂ receptors, monoaminergic receptors, monoamine transporters, and opioid receptors, which results in psychotomimetic affects including hallucinations, agitation, and dysphoria.²²

Sodium-Channel Blockers
Sodium channel blockers function as analgesics through the noncompetitive inhibition of sodium channels and, consequently, of nerve signal propagation.^19,20 Sodium channel blockers consist of two classes: esters (chloroprocaine, procaine, tetracaine) and amides (lidocaine, mepivacaine, ropivacaine, bupivacaine). Whereas ester bonds are more rapidly hydrolyzed, amide bonds are more resistant to clearance and thus offer a longer duration of action. Historically lidocaine has been utilized for the treatment of ​chronic​ ​neuropathic​ ​pain, but more​ ​recently ​lidocaine​ ​has​ ​been​ ​studied​ ​for​ ​renal​ ​colic,​ ​headache,​ ​and in the perioperative setting.²¹ The expanse of utility stems from lidocaine’s analgesic, anti-hyperalgesic, and anti-inflammatory properties. Lidocaine is a sodium channel blocker that slows the flow of sodium ions across the cell membrane, lessening the influx of calcium ions into the nerve terminals and inhibiting the release of the excitatory neurotransmitter “glutamate.” This reduces spontaneous nerve firing, causing a decrease in the sensation of pain.⁴¹

Intravenous lidocaine can be given as a bolus of 1-2 mg/kg (maximum 200 mg) or as a continuous infusion of 0.5-3 mg/kg/hr based on ideal body weight.²⁸ Administering the bolus dose prior to initiating the continuous infusion may result in faster time to therapeutic effect.

Lidocaine is a Vaughn Williams Class IB antiarrhythmic and there is the potential of developing cardiac arrhythmias. Although the risk is low it does increase with higher dosages and accumulation in the setting of liver dysfunction. More common adverse effects include dizziness and paresthesias.²⁷ Serum levels of lidocaine can be obtained; however, this is a send-out laboratory test for many hospitals resulting in a lag time of 48 hours or greater. If lidocaine levels are obtained, the desired concentration to avoid unwanted side effects is less than 4 mcg/mL.

Dopamine Receptor (D1-R, D2-R) Antagonist
Dopamine receptor antagonists including metoclopramide, prochlorperazine, chlorpromazine, haloperidol, and droperidol provide analgesia through the modulation of the dopamine-centered pain signaling pathways.²⁹

Metoclopramide, prochlorperazine, chlorpromazine, and droperidol has all been shown to effectively treat acute migraines.^30-34 Droperidol and haloperidol have also been shown to be efficacious in the treatment of gastroparesis, cannabinoid-induced hyperemesis, and cycling vomiting syndrome.^35,36

Side effects of dopamine-receptor antagonists include QT prolongation, extrapyramidal side effects (akathisia, dystonia), anti-muscarinic effects (drowsiness, dry mouth, constipation, hypotension), and neuroleptic malignancy syndrome (hyperpyrexia, muscle rigidity, rhabdomyolysis) (Vinson, 2001; D’Souza, 2018).

Metoclopramide, prochlorperazine, and chlorpromazine can be administered over a 15 to 30 minute infusion to reduce extrapyramidal effect (Bigal, 2002; D’Souza, 2018). 25 mg IV or PO diphenhydramine may also be used with prochlorperazine to offset the associated akathisia.^37,38

Dexmedetomidine
The alpha-2-adrenergic receptor agonist dexmedetomidine produces analgesia by dampening the centrally-activated sympathetic (adrenergic) pathway.³⁹ Dexmedetomidine utilization has expanded from it classic role as a sedative among mechanically ventilated patients in intensive care settings, to a promising analgesic adjunct outside the ICU.³⁹ Concomitant DXMT use has been shown to reduce opioid (oxycodone) consumption, decrease opioid side effect profile, and improve patient satisfaction in the postoperative setting.⁴⁰ Dexmedetomidine can be delivered IV or IN with recommended dosing of 0.5 to 1.0 μg/kg IV (1 to 2 μg/kg intranasal).³⁹ At this time of this review, a high cost and reduced availability in the has limited research and utilization of DXMT in the emergency setting and its use remains an emerging concept inneed of further research.

Adjunct Agents for Neuropathic Pain

Anticonvulsants
Gabapentin and pregabalin are effective treatments for post hepatic neuralgia, phantom limb pain, peripheral neuropathy, and pain caused by nerve compression. Gabapentin and pregabalin have the same binding site on the α₂-δ subunit of presynaptic, voltage-dependent calcium channels that are located throughout the peripheral and central nervous systems. Similar to lidocaine, blocking the calcium channels reduces the flow of calcium ions into the nerve terminals and inhibits the release of the excitatory neurotransmitter "glutamate" and nerve cell excitability.⁴² A common misconception is that these agents alter GABA uptake and degradation however, they are inactive at GABA_A and GABA_B receptors, and are not converted metabolically into GABA or a GABA antagonist.

Although gabapentin and pregabalin have the same pharmacologic profile, the binding affinity for the α₂-δ subunit, and potency, of pregabalin is six times more than that of gabapentin.⁴³ Gabapentin also has variable interindividual bioavailability with saturable oral absorption, meaning that its bioavailability decreases as the dose increases (Neurontin PI). Therefore, smaller doses, given more frequently, may be required to optimize absorption. Pregabalin has a more predictable, linear pharmacokinetic profile that is not saturable (Pregabalin PI).

Important: Gabapentin and pregabalin may be initiated in the emergency department but the onset of pain relief is not typically seen immediately. These agents require a slow titration to effect over several weeks. As a result, they should be started at a low dose and titrated based upon clinical effect, renal function, and presence of adverse effects by an outside provider. Additionally, neither gabapentin nor pregabalin should be administered with opioids as both may potentiate the euphoric effects of opioids when taken concomitantly, increasing susceptibility to abuse (100) and a worsening respiratory and CNS depression.

Example Dosing/Titration/Therapeutic switch of Pregabalin

• Dosing in diabetic peripheral neuropathy
  • Begin at 50 mg PO three times daily and increase to 100 mg three times daily within 1 week based on efficacy and tolerability.
• Dosing in postherpetic neuralgia
  • Begin at 75 mg PO twice a day or 50 mg three times daily and increase to 100mg three times daily within 1 week based on efficacy and tolerability. Dosing may be further escalated over 2–4 weeks to a maximum of 300 mg twice a day, or 200 mg three times daily.
• Converting to Pregabalin: Gabapentin should be discontinued over a minimum of 1 week before starting pregabalin at a dose of 50 mg three times daily. You may also add pregabalin to gabapentin during the titration, but side effects may be additive.

Antidepressants
Antidepressants may be used to treat chronic neuropathic pain typically at lower doses than those given for antidepressant effects. Tricyclic antidepressants (TCAs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) have the most available data.

TCAs with SNRI activity including amitriptyline (tertiary amines) and nortriptyline (secondary amine) as well as the SNRI inhibitor duloxetine are commonly used for neuropathic pain. The exact mechanism of pain relief is not fully understood, but the theory is that the descending inhibitory pathways are potentiated by inhibiting the reuptake of serotonin and norepinephrine in the spinal synapses between first-order and second-order neurons.^47,48 Additionally, serotonin’s activation of metabotropic receptors and norepinephrine’s binding to alpha adrenergic receptors can increase the release of endogenous opioids.⁴⁹

Caution should be taken with the TCAs, especially in the elderly population, due to their strong anticholinergic activity resulting in dizziness, drowsiness, dry mouth, nausea, constipation, and cardiotoxicity, particularly in the elderly population. Additional adverse effects include paresthesias, flushing, palpitations, fatigue, transient neck tightness, chest pressure, and dysrhythmias.^94,95

Triptans
Triptans have high agonist activity on 5-HT_1b,1d receptors resulting in vasoconstriction of intracranial blood vessels, inhibition of vasoactive neuropeptide release, and blocking transmission of pain signals.^50-53 The pharmacokinetic properties of the triptans differ depending on their bioavailability, CNS penetration, route of administration, and metabolic pathways. However, pharmacokinetic differences have shown little impact on clinical efficacy, but may influence the preference of the patient.^64,65 Therefore, the American Academy of Neurology supports the role of all the triptans in the abortive management of moderate-to-severe migraines.⁶⁶ (Silberstein, 2000), and if the patient fails or develops intolerance to one triptan a trial of an alternative agent should be performed.⁶⁷

Contraindications to the triptans stem from their vasoconstrictive properties including cardiac ischemia that has been reported in patients with and without a CV history.¹²⁷ Although unclear whether the etiology is a result of a true vascular pathology, the triptans are contraindicated in patients with coronary artery disease, cerebrovascular disease, uncontrolled hypertension, rhythm disturbances, peripheral vascular disease, ischemic bowel disorders, and hemiplegic or basilar migraine (Triptan PIs). 

Topical Analgesic Agents
Topical/transdermal preparations are an attractive option to reduce systemic adverse effects of medications while providing pain relief for conditions such as sprains, strains, tendinopathies, as well as several neuropathic conditions like post-herpetic neuralgia, burns, and arthritic flares. In addition to limited system absorption that ranges from 0.2% to 8% of the oral route, topic NSAIDs can accumulate in cartilage and tendons resulting in higher localized concentrations.⁷⁶ Keep in mind that topical preparations can only penetrate 8–10 mm and are most useful in well-localized neuropathic and inflammatory pain. 

Examples of topical analgesic agents include:

• Lidocaine topical: 2-5%; cream, gel, ointment
• Lidocaine patch: 5% prescription patch or 4% OTC patch
• Capsaicin patch (8%) and cream (0.025 to 0.075%)
• Diclofenac: gel, solution, patch
• Ketoprofen
• Methyl salicylate-menthol ointment

Opioid Analgesia
Opioids may be used in the treatment of traumatic injuries, visceral pain, vaso-occlusive crisis, and cancer related pain. Opioids mimic the body’s own analgesic system with a similar molecular structure as endogenous opioids.

There are 3 classes of opioids, with the naturally occurring category derived from opium. Semi-synthetic opioids have been chemically modified from the natural opiates, and synthetic opioids are entirely chemically manufactured. Knowing the classification of agents may help with selection when faced with patient reported opioid allergies or intolerances.

There are three types of opioid receptors: mu, kappa, and delta with the mu receptor primarily responsible for the analgesic effect. Of note, tramadol also inhibits reuptake of serotonin and norepinephrine in addition to weak mu receptor binding.

Activation of the mu receptor also triggers respiratory depression and physical dependence, which have not been associated with delta and kappa receptor activation.⁷⁷ Opioids can also activate mast cell degranulation leading to histamine release and subsequent flushing, urticaria, pruritus, and/or hypotension. However, not all opioids produce the same level of histamine release with morphine and codeine having the highest and fentanyl and hydromorphone inducing little to no release.

Morphine
Morphine is considered the gold standard and the baseline for which all other opioids are measured.¹²¹ Similar to other opioids, morphine derives its effects by preferentially activating the mu-opioid receptors (MOR).^103,111,126

Morphine undergoes significant first-pass metabolism in the liver with 20-25% overall oral bioavailability.¹⁰⁴ Compared with more lipid-soluble opioids such as codeine, heroin, and methadone, morphine crosses the blood-brain barrier at a considerably lower rate.⁹⁵ Morphine is metabolized by the liver through glucuronidation (UDP glucuronosyltransferase, UGT2B7) to active metabolites morphine-6-glucuronide (M6G) and morphine-3-glucuronide (M3G).⁹² M6G is a more potent analgesic version of morphine.^115,117 M3-G has less affinity for opioid receptors but causes neuroexcitatory effects (allodynia, myoclonus, seizures) (Smith 2000). Morphine metabolism is independent of the CYP-mediated metabolism, effectively avoiding these drug-drug metabolism interactions.¹²² However, similar to the allelic variation seen with CYP2D6 enzymatic activity, variability exists among UGT2B7 enzyme metabolism and should be considered in patients who appear ultrasensitive, or conversely unresponsive, to standard doses of morphine.^88,93,98

Following metabolism, morphine metabolites are renally excreted with a small amount excreted as the parent compound.^97,105 Morphine metabolites (M3G and M6G) may accumulate in renal failure resulting in significant toxicity.⁹⁷ Morphine should be used cautiously in patients with renal disease and elderly patients with decreased renal function.^{97,105,116,118}

Fentanyl
Fentanyl is metabolized by the liver through dealkylation (CYP3A4) producing inactive metabolites that are renally excreted.^101,119 Drug-drug interactions can occur secondary to competition for CYP3A4 metabolism. Fentanyl should be used cautiously with CYP3A4 competing substrates and inhibitors like statins, amiodarone, haloperidol, macrolides, azole antifungals (fluconazole, ketoconazole), calcium channel blockers, grapefruit juice (bergamottin), methylprednisolone, and protease inhibitors (indinavir, ritonavir).^120,122 The metabolism of fentanyl to inactive metabolites allows for safe use in patients during renal failure or dialysis.⁹⁷

In addition to the common opioid side effects such as respiratory depression, fentanyl toxicity can result in muscle (chest wall) rigidity.^87,90 In contrast to other opioids, fentanyl does not result in histamine-induced hypotension making its use safe in hemodynamically compromised patients.¹¹⁴

Hydromorphone
Similar to oxymorphone and morphine sulfate, hydromorphone (HM) is independent of CYP450 metabolism, avoiding these drug-drug interactions.^122,125 HM undergoes hepatic glucuronidation producing the primary metabolite, hydromorphone-3-glucuronide (H3G). Similar to morphine metabolite M3G, H3G is neuroexcitatory and excessive buildup can lead to myoclonus and seizure activity.^122-124

HM and its metabolites are renally excreted and should be cautiously administered in patients with renal disease or dialysis.^97,105,112 HM metabolites are more efficiently dialyzed than morphine metabolites and thus better tolerated among patients on dialysis.^97,105

Side effects of HM are dose-dependent and similar to general opioids.¹¹² If pruritus becomes intolerable, administration of oral diphenhydramine, not IV, may be considered as the latter potentiates sedation while offering limited pruritic relief.¹⁰⁶

Oxycodone/ Hydrocodone
Oxycodone (OC) and hydrocodone (HC) were both marketed with the advantage of reduced first pass metabolism over oral morphine.⁹⁹ Both OC and HC are metabolized in the liver (CYP2D6, CYP3A4) to their active metabolites oxymorphone and hydromorphone.¹²² Metabolic variability exists among these enzymes resulting in ineffective analgesia in the “poor metabolizers” and toxic levels in the “ultra-rapid metabolizers”.^99,100 Similar to morphine, the active metabolites of oxycodone and hydrocodone accumulate in renal failure and should be used cautiously in patient with renal disease and elderly patients with decreased renal function.^{97,105,116,118}

Codeine
Codeine is a prodrug with analgesic effects dependent on the metabolic conversion from the prodrug form to codeine-6-glucuronide (C6G) and morphine by the liver CYP450 enzyme CYP2D6 (similar to tramadol). This enzymatic reaction has significant allelic variability.^102,122 Both poor and ultra-rapid metabolizers exist among the population with up to 10% of population lacking the enzyme necessary for codeine conversion and 1-7% of the Caucasian population being ultrarapid codeine metabolizers.^{86,99,102,108} This variation results in uncontrolled variability in analgesic response. Nursing mothers may also produce breast milk containing higher than expected levels of metabolites that can lead to severe adverse events in nursing infants.⁹⁶

In addition to varying side effect profiles, onset of action and potency differs between opioid analgesics. For example, morphine has low lipid solubility and slow blood-brain barrier penetration resulting in a slow onset of action. On the other hand, fentanyl is highly lipid soluble, resulting in a very rapid onset of action.⁷⁸ Furthermore, hydromorphone and fentanyl exhibit the highest mu receptor affinity resulting in the greatest analgesic effects.

Opioid Conversion Tips

• First calculate the morphine equivalent of the opioid being converted from, and then calculate the dose of the opioid being converted to based on the morphine equivalent
• When converting patients from one opioid to another decrease the dose of the new opiate by 25-50% (after calculations) due to incomplete cross-reactivity between opiates

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