Prescriptions with Precision

The use of pain medications with distinct mechanisms of action exemplifies precise prescribing aimed at enhancing pain relief, reducing side effects, and improving the patient experience in both acute and chronic pain. A thorough understanding of pharmacologic mechanisms, dosing, and potential adverse effects is essential for individualized patient-centered treatment. Commonly used medications such as acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, gabapentinoids, antidepressants (ie, serotonin-norepinephrine reuptake inhibitors and tricyclic antidepressants), and muscle relaxants may be used alone or in combination to achieve safe and effective pain control.

Key points

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Acetaminophen and nonsteroidal anti-inflammatory drugs are nonopioid analgesics that aid in the management of both acute and chronic pain when liver and renal function permit.
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Opioids are a first-line treatment option for acute, severe pain, however limited in chronic pain due to side effects including constipation, tolerance, withdrawal, and misuse potential.
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Pregabalin and gabapentin are 2 commonly used medications for neuropathic pain with similar mechanisms of action; however, pregabalin has the advantage of enhanced gastrointestinal absorption.
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Tricyclic antidepressant and serotonin-norepinephrine reuptake inhibitor classes are useful in chronic pain conditions, and it is important to consider side effect profile with selection.
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The musculoskeletal relaxant class contains medications with different mechanisms of action to manage painful muscle spasms as well as spasticity.

Abbreviations

BUN	blood urea nitrogen
CNS	central nervous system
COX	cyclooxygenase
COX-2	cyclooxygenase-2
CR	controlled release
CrCl	creatinine clearance
FDA	Food and Drug Administration
GABA	gamma-aminobutyric acid
GI	gastrointestinal
IR	immediate release
IV	intravenous
NAPQI	N-acetyl-p-benzoquinone imine
NSAIDs	nonsteroidal anti-inflammatory drugs
OTC	over the counter
qid	4 times a day
Rx	prescription
SNRIs	serotonin-norepinephrine reuptake inhibitors
SR	sustained release
TCAs	tricyclic antidepressants
tid	3 times a day
XR	extended release

Introduction

The selection of pharmacologic treatments for pain management is guided by multiple factors, including the specific pain diagnosis and the presence of comorbid conditions. Common medications used in the treatment of acute and chronic pain include acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), opioids, and agents used for muscle spasms and neuropathic pain.

Acute pain is often considered the body’s alarm system, signaling real or potential tissue injury through activation of peripheral or visceral nociceptors. This nociceptive input initiates a complex cascade of events, commonly referred to as the “inflammatory soup,” which involves the release of cytokines, prostaglandins, bradykinin, and other mediators that sensitize nociceptors and contribute to primary hyperalgesia. These mechanisms create a therapeutic window in which targeted interventions can modulate the underlying biologic processes and promote recovery.

In contrast, chronic pain represents a maladaptive continuation of pain beyond the anticipated duration of healing, often characterized by central sensitization and altered pain modulation. It may be perpetuated by prior injury, unresolved acute pain, psychosocial stressors, and negative affective states, forming a self-reinforcing loop. From a neurobiological perspective, chronic pain engages neural circuits involved in memory, emotion, and threat detection, reflecting the brain’s attempt to anticipate or guard against further harm.

Effective treatment requires a multimodal strategy that combines pharmacologic agents with the specific pain mechanism involved, while minimizing the risk of polypharmacy and adverse effects. This approach requires a sound understanding of pharmacologic mechanisms of action, side effect profiles, and how they intersect with individual patient factors and comorbidities ( Fig. 1 ). ^,

A diagram shows the anatomical pain perception pathway from peripheral trauma to the brain, alongside a list of pharmacological and nonpharmacological interventions. — Fig. 1

Discussion

Acetaminophen (APAP, N-acetyl-p-aminophenol)

Acetaminophen is a well-studied and commonly used antipyretic that reduces fever by acting directly on the hypothalamic heat-regulating center. It is also widely used as an analgesic for pain related to arthralgia, dental procedures, dysmenorrhea, headache, musculoskeletal injuries, myalgia, and osteoarthritis, and is frequently used off-label for headaches. Acetaminophen’s actions are thought to occur primarily within the central nervous system (CNS), where it inhibits the cyclooxygenase (COX) pathway, specifically COX-1 and COX-2 enzymes involved in prostaglandin (PG) synthesis. While this central COX inhibition may account for part of its analgesic and antipyretic effects, additional mechanisms have been proposed. Notably, acetaminophen is also metabolized into AM404, a well-characterized compound formed in the brain and spinal cord. AM404 is believed to contribute to analgesia through multiple mechanisms including activating TRPV1 receptors, indirectly modulating CB1 receptors, inhibiting peripheral sodium channels (NaV1.7 and NaV1.8), and enhancing serotonergic descending pain pathways. ^,^,^,

Epidemiology studies have not clearly associated acetaminophen use during pregnancy with birth defects, miscarriage, or maternal/fetal adverse outcomes. The American College of Obstetricians and Gynecologists and Society for Maternal-Fetal Medicine recommend acetaminophen as the first-line pharmacologic therapy for pain and/or fever during pregnancy; however, with the precaution of using it at the lowest effective dose for the shortest possible time. ^,^,

Multiple formulations of acetaminophen are available including the oral route, which has rapid absorption from the gastrointestinal (GI) tract, rectal route, which has prolonged absorption, and intravenous (IV) route, which can result in higher plasma concentrations. Certain products may contain additives; chewable tablets often contain aspartame that can affect individuals with phenylketonuria and chewable gels may contain sugar and sodium, which may be a concern in patients with diabetes and hypertension.

Recommended dosages of APAP typically may range from 325 mg to 650 mg every 4 hours as needed or 1000 mg taken every 6 hours, not to exceed total daily dose of 4000 mg, limits based on the potential for liver toxicity. Special caution should be taken when combination medications that contain APAP are used. To improve safety further, manufacturers have lowered the recommended maximum daily dose to not exceed 3000 mg. Acetaminophen may be utilized as an adjunct in a comprehensive multimodal pain management treatment algorithm. It is primarily metabolized in the liver by glucuronidation, sulfate conjugation and by cytochrome P450 oxidation. Strong precautions are suggested in liver disease, alcohol use, and severe renal impairment (creatinine clearance 10–30 mL/min). Excessive intake can cause severe/fatal hepatic dysfunction. The IV route is contraindicated in patients with severe hepatic impairment or active hepatic disease.

Acetaminophen-induced hepatotoxicity during overdose is related to the buildup of the metabolite N-acetyl-p-benzoquinone imine (NAPQI). Tobacco use can worsen NAPQI build-up as tobacco can impact drug metabolism via CYP1A2. In cases of chronic use or acute toxicity, checking a baseline liver function test and serum creatinine/blood urea nitrogen (BUN) is appropriate.

Nonsteroidal Anti-inflammatory Drugs

NSAIDs are a class of medications that have analgesic, anti-inflammatory, and antipyretic effects that treat acute or chronic pain including pain related to ankylosing spondylitis, dysmenorrhea, gout, juvenile idiopathic arthritis, migraine, muscular aches, osteoarthritis, and rheumatoid arthritis. ^,^,^,^,^, NSAIDs work by inhibiting cyclooxygenase and lipoxygenase, either nonspecifically or selectively, to decrease prostaglandin (PG) synthesis. PG mediates inflammation, sensitizes afferent nerves, and potentiates the action of bradykinin, thus inducing pain. ^,^,

Multiple formulations of NSAIDs are available including oral, IV, intramuscular, and topical preparations. Topical products may be preferred for less systemic side effects.

NSAIDs can be classified based on chemical structures and mechanisms of action ( Fig. 2 ):

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Carboxylic acid derivatives contain a carboxylic acid group in the molecular structure and can be further subdivided into propionic acid derivatives (ie, ibuprofen, naproxen, ketoprofen, fenoprofen, and flurbiprofen), acetic acid derivatives (ie, diclofenac, indomethacin, ketorolac, sulindac, and tolmetin), and salicylates (ie, aspirin). Aspirin’s antiplatelet effects are due to nonreversible acetylation of COX enzymes.
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Enolic acid derivatives contain an enol group (type of alcohol) and can be subdivided into oxicams (ie, piroxicam, meloxicam, and tenoxicam) and pyrazolones (ie, phenylbutazone).
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Napthyl-alkanes have naphthalene rings in their structure (ie, nabumetone [a prodrug])
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COX-2 selective agents (ie, celecoxib and etoricoxib) only inhibit the cyclooxygenase-2 (COX-2) enzyme associated with pain and inflammation and is thought to have less GI side effects. Rofecoxib and valdecoxib were both withdrawn from the market due to cardiovascular and dermatologic risks.

A flowchart illustrates the classification of nonsteroidal anti-inflammatory drugs into carboxylic acid, enolic acid, napthyl-alkanone, and cyclooxygenase two inhibitors. — Fig. 2

Recommended dosages vary for the many different NSAID options that are available, and guidance is per product/package insert. NSAIDs may be utilized as an adjunct in a comprehensive multimodal pain management treatment algorithm. NSAIDs can provide a synergistic effect when used in conjunction with opioids for severe pain control. They can facilitate the lowest effective opioid dosing with the “door handle analogy,” which effectively decreases pain related to inflammation and allows for improved opioid attenuation of remaining pain signals. See Table 1 for common NSAID dosing. Caution is recommended because of the broad range of side effects, which can affect nearly every organ system and vary in severity, along with a high potential for drug–drug interactions. Baseline renal function, including serum creatinine and BUN, should be obtained and monitored regularly.

Table 1

Common nonsteroidal anti-inflammatory drug dosing

Medication	Starting Dose	Usual Dosing Range	Other
Aspirin	325 mg 3 times a day	325–650 mg 4 times a day	Doses of 3600 mg/d are needed for anti-inflammatory activity
Celecoxib	100 mg daily	100 mg twice daily or 200 mg daily	—
Diclofenac XR Diclofenac IR	100 mg daily 50 mg twice a day	100–200 mg daily 50–75 mg twice a day	—
Etodolac	300 mg twice a day	400–500 mg twice a day	—
Ibuprofen	200 mg 3 times a day	1200–3200 mg/d in 3 to 4 divided doses	Available OTC and Rx
Indomethacin Indomethacin SR	25 mg twice a day 75 mg SR once daily	Titrate dose by 25–50 mg/d until pain controlled or maximum dose of 50 mg 3 times a day Can titrate to 75 mg SR twice daily if needed	—
Ketoprofen	50 mg 3 times a day	50–75 mg 3 to 4 times a day	—
Meloxicam	7.5 mg daily	15 mg daily	—
Naproxen	250 mg twice a day	500 mg twice a day	Available OTC and Rx
Naproxen sodium Naproxen sodium CR	220 mg twice a day	220–550 mg twice a day 375–750 mg twice a day	—
Salsalate	500 mg twice a day	500–1000 mg 2 to 3 times a day	—

Abbreviations: CR, controlled release; IR, immediate release; OTC, over the counter; Rx, prescription; SR, sustained release; XR, extended release.

Opioids

Opioids provide pain relief by binding to mu, kappa, and delta opioid receptors in the CNS, thus inhibiting the propagation of ascending pain signals. Common opioid medication dosing, metabolism, and other considerations are provided in Table 2 . Opioids are an effective treatment of acute pain management and continue to be a mainstay of treatment intraoperatively, for cancer-related pain, and end-of-life care. The Centers for Disease Control and Prevention and the Veterans Administration/Department of Defense chronic pain guidelines do not recommend routine use of long-term opioid treatment of chronic noncancer pain due to lack of long-term safety and efficacy evidence. ^, Should long-term opioid therapy be prescribed, risk mitigation strategies should be utilized including long-term opioid consents or agreements, urine toxicology testing, naloxone prescribing, and review of the state prescription drug monitoring program.

Table 2

Common opioid dosing, metabolism, and other considerations ^,^,^,

Medication	Usual Dosing	Metabolism	Other Considerations
Morphine	PO 5–30 mg every 4 h IM 5–20 mg every 4 h IV 5–15 mg every 4 h SR 15–30 mg every 12 h (some patients may need dosing every 8 h)	Glucuronidation via UGT2B7	Medication of choice in severe pain, use with caution in renally compromised patients
Hydromorphone	PO 2–4 mg every 4–6 h IM 1–2 mg every 4–6 h IV 0.5–2 mg every 4 h	Glucuronidation via UGT2B7	Use in severe pain
Codeine	PO 15–60 mg every 4–6 h	CYP2D6	Use in mild-to-moderate pain, weak analgesic. It is a prodrug
Hydrocodone	PO 5–10 mg every 4–6 h	CYP2D6	Use in moderate/severe pain
Oxycodone	PO 5–15 mg every 4–6 h CR 10–20 mg every 12 h	CYP3A4 and CYP2D6	Use in moderate/severe pain
Fentanyl	Transdermal 25 mcg/h every 72 h (starting dose) IV 25–50 mcg/h IM 50–100 mcg every 1–2 h Transmucosal, intranasal, and sublingual dosing based off of individual product	CYP3A4	Use in severe pain. Do not use transdermal patch in acute pain Follow product-specific initiation and titration dosing recommendations
Methadone	PO 2.5–10 mg every 8–12 h	CYP3A4, CYP2B6, CYP2C8, CYP2C19, CYP2D6, and CYP2C9	Effective in severe chronic pain Equianalgesic dose of methadone when compared with other opioids will decrease progressively the higher the previous opioid dose Methadone prescribed for maintenance or detoxification treatment must be dispensed under a Substance Abuse and Mental Health Services administration—certified opioid treatment program
Buprenorphine	Transdermal delivery system 5, 7.5, 10, 15, 20 mcg/h every 7 d Buccal film 75 mcg every 12 h to 900 mcg every 12 h IM 0.3 mg every 6 h IV (slow) 0.3 mg every 6 h	CYP3A4	Mu opioid partial agonist May precipitate withdrawal in opiate-dependent patients Detailed manufacturer dosing conversion recommendations exist
Tramadol	PO 50–100 mg every 4–6 h ER 100 mg every 24 h	CYP3A4 and CYP2D6	Maximum dose for nonextended release, 400 mg/24 h; maximum for extended release, 300 mg/24 h Decrease dose in patients with renal impairment and in the elderly

Abbreviations: CR, controlled release; ER, extended release; IM, intramuscular; IV, intravenous; PO, oral; SR, sustained release.

Common adverse effects of opioid agents include constipation, sedation, nausea, vomiting, urticaria, pruritis, mood changes (euphoria and dysphoria), hypogonadism, and physical dependence. Opioid medications also carry the risk of addiction and potentially fatal respiratory depression. Caution should be taken when prescribing opioids for either acute or chronic use, especially in patients who have a history of substance use disorders or those who may have underlying respiratory, renal, or hepatic conditions.

Gabapentinoids

The gabapentinoids class consists of gabapentin and pregabalin. Both medications bind to the α2δ subunit of voltage-gated calcium channels inhibiting calcium influx and subsequent release of neurotransmitters to impact pain. ^, Table 3 lists the indications, pharmacokinetics, and dosing of gabapentin and pregabalin. One key difference between these 2 medications is the mechanism of absorption. Both gabapentin and pregabalin are absorbed in the small intestine, with pregabalin additionally absorbed in the proximal colon. The absorption of gabapentin is dependent on the l -amino transport system, which is saturable, and as such, the dose of gabapentin and the subsequent plasma area under the curve do not rise proportionally. Conversely, pregabalin has nonsaturable absorption in a linear manner and it does not only rely on the l -amino transport system for absorption from the GI lumen. The 2 previously described mechanisms allow for pregabalin to have higher bioavailability.

Table 3

Pregabalin and gabapentin characteristics ^,^,

	Gabapentin		Pregabalin
FDA-approved indications (pain related)	Postherpetic neuralgia		Fibromyalgia, neuropathic pain associated with diabetic peripheral neuropathy, neuropathic pain associated with spinal cord injury, and postherpetic neuralgia
Off-label indications (pain related)	Fibromyalgia and neuropathic pain (other than postherpetic neuralgia)		Cancer-associated neuropathy and neuropathic pain in critically ill patients
Common dosing	900–3600 mg/d		150–600 mg/d
Suggested frequency	Three to 4 times a day		Two to 3 times a day
Maximum dosing in renal impairment- CrCl (mL/minute)	>79	3600 mg/d in 3 divided doses	≥60	600 mg/d in 2–3 divided doses
	50–79	1800 mg/d in 3 divided doses	30–59	300 mg/d in 2–3 divided doses
	30–49	900 mg/d in 2–3 divided doses	15–29	150 mg/d in 1–2 divided doses
	15–29	600 mg/d in 1–2 divided doses	<15	75 mg/d in 1 dose
	<15	300 mg/d in 1 dose
T _max (hours)	2–3		1
t _1/2 (hours)	5–7		5.5–6.7
Bioavailability	27%–60%		>90%
Pharmacokinetics	Nonlinear (zero-order)		Linear
Plasma protein binding	<3%		Assumed to be 0
Metabolism	Not metabolized		Negligible
Renal excretion	100% unchanged		92%–99% unchanged